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1.
Lancet Oncol ; 2020 May 13.
Artigo em Inglês | MEDLINE | ID: mdl-32416073

RESUMO

BACKGROUND: Patients with advanced or metastatic oesophageal squamous cell carcinoma have poor prognosis and few treatment options after first-line therapy. We aimed to assess efficacy and safety of the anti-PD-1 antibody camrelizumab versus investigator's choice of chemotherapy in previously treated patients. METHODS: ESCORT is a randomised, open-label, phase 3 study of patients aged 18 to 75 years with a histological or cytological diagnosis of advanced or metastatic oesophageal squamous cell carcinoma done at 43 hospitals in China. Eligible patients had an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1, and had progressed on, or were intolerant to, first-line standard therapy. Patients were randomly assigned (1:1) to camrelizumab (200 mg every 2 weeks) or chemotherapy with docetaxel (75 mg/m2 every 3 weeks) or irinotecan (180 mg/m2 every 2 weeks), all given intravenously. Central randomisation was done using the Randomization and Trial Supply Management system with block size randomly generated as four or six and stratified by disease and ECOG performance status. The primary endpoint was overall survival, assessed in randomised patients who had received at least one dose of treatment. Safety was assessed in all treated patients. The trial is registered with ClinicalTrials.gov, NCT03099382, and is closed to new participants. FINDINGS: From May 10, 2017, to July 24, 2018, 457 (75%) of 607 screened patients were randomly assigned to treatment, of whom 228 received camrelizumab treatment and 220 received chemotherapy. As of data cutoff on May 6, 2019, with a median follow-up time of 8·3 months (IQR 4·1-12·8) in the camrelizumab group and 6·2 months (3·6-10·1) in the chemotherapy group, median overall survival was 8·3 months (95% CI 6·8-9·7) in the camrelizumab group and 6·2 months (5·7-6·9) in the chemotherapy group (hazard ratio 0·71 [95% CI 0·57-0·87]; two-sided p=0·0010). The most common treatment-related adverse events of grade 3 or worse were anaemia (camrelizumab vs chemotherapy: six [3%] vs 11 [5%]), abnormal hepatic function (four [2%] vs one [<1%]), and diarrhoea (three [1%] vs nine [4%]). Serious treatment-related adverse events occurred in 37 (16%) of 228 patients in the camrelizumab group, and in 32 (15%) of 220 patients in the chemotherapy group. Ten treatment-related deaths occurred, seven (3%) in the camrelizumab group (three deaths from unknown causes, one enterocolitis, one hepatic function abnormal, one pneumonitis, and one myocarditis) and three (1%) in the chemotherapy group (two deaths from unknown causes, and one gastrointestinal haemorrhage). INTERPRETATION: Second-line camrelizumab significantly improved overall survival in patients with advanced or metastatic oesophageal squamous cell carcinoma compared with chemotherapy, with a manageable safety profile. It might represent a potential option of standard second-line treatment for patients with oesophageal squamous cell carcinoma in China. FUNDING: Jiangsu Hengrui Medicine.

3.
BMC Cancer ; 19(1): 1049, 2019 Nov 06.
Artigo em Inglês | MEDLINE | ID: mdl-31694577

RESUMO

BACKGROUND: Diffuse large B-cell lymphoma (DLBCL) is characterized by its clinical and biological heterogeneity. The clinical prognostic implications of tumor-associated macrophages (TAMs) in DLBCL remain controversial and the correlation between TAMs and peripheral absolute monocyte count (AMC) has not yet been elucidated. METHODS: In 221 untreated, newly diagnosed patients with DLBCL, we evaluated the prognostic value of TAMs using immunohistochemical analysis, as well as the association of TAMs and AMC. RESULTS: We found that high CD68 or high CD163 expression was correlated with clinicopathological characteristics, high CD163 expression was an adverse predictor for both overall survival (OS) [hazard ratio (HR) = 2.265, P = 0.005] and progression- free survival (PFS) (HR = 1.925, P = 0.017) in patients with DLBCL. Patients with high CD68 or high CD163 expression had significantly poorer OS and PFS than those with low CD68 or low CD163 expression, respectively (CD68: OS: P<0.001, PFS: P<0.001; CD163: OS: P<0.001, PFS: P<0.001), even in the rituximab era. Moreover, high-risk patients could be further identified by the expression of CD68 or CD163, especially in those classified as low/intermediate risk by International Prognostic Index (IPI). Furthermore, the significant positive correlation was also detected between CD68 expression or CD163 expression and AMC (r = 0.256, P<0.001; r = 0.303, P<0.001). CONCLUSIONS: Patients with high expression of TAMs tend to have poorer OS and PFS, even in the rituximab era, and have positive correlation with AMC. Therefore, the peripheral AMC is a useful prognostic marker reflecting the status of the tumor microenvironment (TME) in DLBCL.

4.
Oncol Lett ; 18(5): 4573-4582, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31611965

RESUMO

Gastric cancer (GC) is one of the most common malignant tumors worldwide. Previous studies have reported that aldehyde dehydrogenase-1A1 (ALDH1A1) and cluster of differentiation (CD)-133 are considered to be cancer stem cell markers in GCs. The present study immunohistochemically examined the distribution and expression of two tumor stem cell markers, CD133 and ALDH1A1, in both primary tumors and para-tumor tissues. In 91 cases with stage III, 57 (62%) were positive for ALDH1A1 and 60 (66%) were positive for CD133. ALDH1A1 was detected in para-tumors and cancerous tissues of the stomach, and the immunoreactivity of the tumors was stronger than that in para-tumor tissues. CD133 was only detected in tumors. The expression of ALDH1A1 was significantly associated with advanced T/N stage (T stage, P=0.012; N stage, P=0.023) and poor differentiation (P=0.020), while CD133 was associated with advanced T stage (P=0.007). Univariate and multivariate Cox proportional hazards analysis revealed that tumor stage, CD133 expression, vascular invasion and sex were independent predictors of disease-free survival (DFS) time, and tumor size, vascular invasion and sex were independent predictors of overall survival (OS) time in patients with GC. Patients with CD133+ GC had poorer DFS (P=0.042), while ALDH1A1+ GC was not associated with poorer DFS. In regard to chemotherapy, improvements in survival were not observed after the addition of taxane compared with two-drug therapy. However, the subgroup analysis indicated that in the ALDH1A1- subgroup, and CD133+ and ALDH1A1- subgroups, an increased OS was observed in two-drug therapy (P=0.043). The results of the present study indicate that ALDH1A1 and CD133 may play an important role in tumor invasion, metastasis and prognosis, and ALDH1A1- expression does not benefit the taxane-based triple chemotherapeutic regimen in patients with GC.

5.
Oncol Lett ; 18(2): 1607-1616, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31423228

RESUMO

Chemotherapy resistance is a major obstacle to the effective treatment of patients with gastric cancer (GC). Mounting evidence has indicated that the dysregulation of microRNAs (miRNAs) is associated with the sensitivity of cancer cells to chemotherapy. However, the mechanisms underlying miRNA-mediated chemoresistance in GC cells remain to be elucidated. The present study aimed to identify functional miRNAs that may regulate the sensitivity of human GC cells to cisplatin (DDP) treatment. miRNA microarray analysis was used to identify differentially expressed miRNAs between the human cisplatin-sensitive GC cell line SGC7901 and the corresponding cisplatin-resistant cell line SGC7901/DDP. miRNA (miR)-362-5p, which is associated with numerous types of tumors, was identified to be downregulated in the SGC7901/DDP cell line. However, the biological role of miR-362-5p in SGC7901/DDP cells remains to be explored. The expression level of miR-362-5p was demonstrated to be reduced in SGC7901/DDP cells compared with SGC7901 cells by reverse transcription-quantitative PCR. Upregulation of miR-362-5p significantly increased cisplatin sensitivity and cisplatin-induced apoptosis, whereas downregulation of miR-362-5p attenuated these effects. Databases predicted that suppressor of zeste 12 protein (SUZ12) may function as a target of miR-362-5p. In addition, the mRNA and protein expression levels of SUZ12 in SGC7901/DDP cells were significantly higher compared with SGC7901 cells and negatively associated with miR-362-5p expression. MTT and western blot analysis assays confirmed that knockdown of SUZ12 enhanced cisplatin sensitivity and decreased NF-κB/p65 protein levels in SGC7901/DDP cells. In addition, upregulation of miR-362-5p in SGC7901/DDP cells decreased the protein expression level of SUZ12, whereas downregulation of miR-362-5p increased the SUZ12 expression level. The results of the present study suggested that dysregulated miR-362-5p may target SUZ12 to promote the development of cisplatin resistance and attenuate cisplatin-induced apoptosis. Therefore, miR-362-5p upregulation combined with cisplatin treatment may serve as a promising therapeutic strategy for patients with cisplatin-resistant GC.

6.
Oncol Lett ; 18(1): 145-152, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31289483

RESUMO

Gastric cancer (GC) is one of the most common types of malignant tumor. Due to the lack of effective drugs and the emergence of chemotherapy resistance, patients with GC exhibit a poor prognosis and low survival rate. MicroRNAs (miRNAs/miRs) serve an important role in drug resistance of different types of cancer. They may be suitable for use as biomarkers in the diagnosis, treatment and prognosis of tumors. The present study aimed to investigate the molecular mechanism underlying the ability of miR-200c-3p to reverse drug resistance in a SGC7901/DDP GC cell line, particularly its effects on the ERCC excision repair 3, TFIIH core complex helicase subunit (ERCC3) and ERCC excision repair 4, endonuclease catalytic subunit (ERCC4) proteins in the nucleotide excision repair (NER) pathway. Reverse transcription-quantitative polymerase chain reaction demonstrated that miR-200c-3p expression in cisplatin-resistant SGC7901/DDP cells was lower than in parental SGC7901 cells, whereas the protein expression levels of ERCC3 and ERCC4 in these cells were higher by western blot analysis. In SGC7901/DDP-derived miR-200c-3p overexpressing cells, ERCC3 expression, ERCC4 expression and cisplatin resistance were decreased compared with in parental SGC7901/DDP cells and SGC7901/DDP-derived vector control cells. In SGC7901-derived miR-200c-3p knockdown cells, ERCC3 expression, ERCC4 expression and cisplatin resistance were increased compared with in parental SGC7901 cells and SGC7901-derived vector control cells. In conclusion, overexpression of miR-200c-3p may reverse drug resistance in the SGC7901/DDP GC cell line via downregulation of ERCC3 and ERCC4, which suggested this may be part of a mechanism involving the NER pathway.

7.
BMC Cancer ; 19(1): 650, 2019 Jul 02.
Artigo em Inglês | MEDLINE | ID: mdl-31266459

RESUMO

BACKGROUND: DNA aneuploidy has attracted growing interest in clinical practice. Nevertheless, its prognostic value in gastric cancer patients remains controversial. This meta-analysis aims to explore the impact of DNA ploidy status on the survival of gastric cancer patients. METHODS: We used PubMed and Web of Science databases to retrieve relevant articles. The correlation between DNA aneuploidy and the clinicopathological features of gastric cancer, such as stage, depth of invasion (T), lymph node metastasis (N), distant metastasis (M), differentiation (G), tumor types (Lauren classification) and overall survival (OS) were evaluated. Hazard ratios (HRs) with corresponding 95% confidence intervals (CIs) were collected carefully from each article OS was presented with HRs. The relationships between DNA aneuploidy and each characteristic were analyzed using risk ratios (RR) and a 95% confidence interval (CI). Significance was established using P < 0.05. Funnel plot was conducted to detect the publication bias. RESULTS: After careful selection, 25 studies involving 3449 cases were eligible for further analyses. Patients with DNA aneuploidy were considered at risk of more advanced stages (stage III-IV vs. stages I-II, RR = 1.23; 95% CI, 1.07 to 1.42; P = 0.003), lymph node metastasis (N+ vs. N-: RR = 1.43; 95% CI, 1.12 to 1.82, P = 0.004), and intestinal tumor type (intestinal vs. diffuse: RR = 1.45; 95% CI, 1.02 to 2.06; P = 0.04). And an adverse relation was observed between DNA aneuploidy and tumor differentiation. While no association was found between DNA aneuploidy and distant metastasis (P = 0.42) nor depth of tumor invasion (P = 0.86). Regarding overall survival, aneuploid tumors were associated with worse survival in all patients (P < 0.00001). CONCLUSIONS: We found that DNA aneuploidy was an important predictor for gastric cancer patients, and should be used as a potential biomarker for further classification in gastric cancer.


Assuntos
Aneuploidia , Neoplasias Gástricas/genética , Neoplasias Gástricas/mortalidade , Intervalos de Confiança , DNA de Neoplasias , Humanos , Metástase Linfática , Invasividade Neoplásica , Estadiamento de Neoplasias , Prognóstico , Modelos de Riscos Proporcionais , Neoplasias Gástricas/patologia
8.
J Cancer ; 10(8): 1923-1929, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31205551

RESUMO

Background: This study was initially designed to examine whether oxaliplatin-based regimen was superior to cisplatin-based regimen in tumour remission as first-line chemotherapy for advanced gastric cancer (GC). Methods: Literature in EMBASE, PUBMED, Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, American Society of Clinical Oncology (ASCO) and European Society of Medical Oncology (ESMO) was searched. Only phase II or III randomized controlled trials (RCTs) comparing the effectiveness and safety between oxaliplatin-based and cisplatin-based regimens as first-line treatment for advanced GC were selected. Odds ratios (ORs) with 95% confidence intervals (CIs) were reported. The primary endpoints were complete remission rate (CRR), partial remission rate (PRR), objective response rate (ORR), and disease control rate (DCR). The second endpoint was the toxicity response. Results: 2,140 patients from six phase II or III RCTs were included. Compared to cisplatin-based therapy, subjects who received oxaliplatin-based treatment had significantly higher PRR (OR: 1.25, 95%CI: 1.05-1.48, P=0.01, I2=0%), ORR (OR: 1.21, 95%CI: 1.02-1.44, P=0.03, I2=0%) and DCR (OR: 1.76, 95%CI: 1.31-2.38, P=0.0002, I2=25%), but not CRR (OR: 0.70, 95%CI: 0.37-1.31, P=0.27, I2=0%). In addition, oxaliplatin-based therapy significantly decreased all grades of leukopenia, neutropenia, anemia, febrile neutropenia, nausea, stomatitis, creatinine elevation and thromboembolism, as well as grades 3-4 of leukopenia, neutropenia, anemia and febrile neutropenia than cisplatin-based regimen. However, oxaliplatin-based treatment strikingly increased the risk of thrombocytopenia, sensory neuropathy, diarrhea, fatigue and liver dysfunction. Conclusions: Oxaliplatin-based regimen is superior to cisplatin-based regimen in tumour remission as first-line chemotherapy for advanced GC, and is associated with less toxicity and better tolerability.

9.
Lancet Oncol ; 20(6): 806-815, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-31036468

RESUMO

BACKGROUND: Tucidinostat (formerly known as chidamide) is an oral subtype-selective histone deacetylase inhibitor. In an exploratory study, the combination of tucidinostat with exemestane showed preliminary signs of encouraging anti-tumour activity in patients with advanced hormone receptor-positive breast cancer. To build on these findings, we aimed to assess the efficacy and safety of this combination in a randomised trial in a larger population of postmenopausal patients with advanced, hormone receptor-positive breast cancer. METHODS: We did the randomised, double-blind, placebo-controlled, phase 3 ACE trial at 22 specialist cancer centres in China. Eligible patients were postmenopausal women (aged ≥60 years or aged <60 years if their serum follicle-stimulating hormone and oestradiol concentrations were within postmenopausal ranges) with hormone receptor-positive, HER2-negative breast cancer, whose disease had relapsed or progressed after at least one endocrine therapy (either in advanced or metastatic or adjuvant setting), and who had at least one measurable lesion, adequate organ function, Eastern Cooperative Oncology Group (ECOG) performance status of 0-1, and adequate haematological and biochemical parameters. Endocrine therapy did not have to be the most recent therapy before randomisation, but recurrence or progression after the most recent therapy was a prerequisite. Patients were randomly assigned (2:1) by a dynamic randomisation scheme via an interactive web-response system to receive 30 mg oral tucidinostat or placebo twice weekly. All patients in both groups also received 25 mg oral exemestane daily. Randomisation was stratified according to the presence of visceral metastases (yes vs no). Patients, investigators, study site staff, and the sponsor were masked to treatment assignment. The primary endpoint was investigator-assessed progression-free survival. Efficacy analyses were done in the full analysis set population, comprising all patients who received at least one dose of any study treatment, and safety analyses were done in all patients who received at least one dose of any study treatment and for whom at least one safety case report form was available. This study is registered with ClinicalTrials.gov, number NCT02482753. The study has reached the required number of events for final analysis of the primary endpoint. The trial is no longer enrolling patients, but follow-up for investigation of overall survival is ongoing. FINDINGS: Between July 20, 2015, and June 26, 2017, 365 patients were enrolled and randomly assigned, 244 to the tucidinostat group and 121 to the placebo group. The median duration of follow-up was 13·9 months (IQR 9·8-17·5). Investigator-assessed median progression-free survival was 7·4 months (95% CI 5·5-9·2) in the tucidinostat group and 3·8 months (3·7-5·5) in the placebo group (HR 0·75 [95% CI 0·58-0·98]; p=0·033). The most common grade 3 or 4 adverse events in either group were neutropenia (124 [51%] of 244 patients in the tucidinostat group vs three [2%] of 121 patients in the placebo group), thrombocytopenia (67 [27%] vs three [2%]), and leucopenia (46 [19%] vs three [2%]). Serious adverse events of any cause occurred in 51 (21%) of 244 patients in the tucidinostat group and seven (6%) of 121 patients in the placebo group. No treatment-related deaths were reported. INTERPRETATION: Tucidinostat plus exemestane improved progression-free survival compared with placebo plus exemestane in patients with advanced, hormone receptor-positive, HER2-negative breast cancer that progressed after previous endocrine therapy. Grade 3-4 haematological adverse events were more common in the tucidinostat plus exemestane group than in the placebo plus exemestane group. Tucidinostat plus exemestane could represent a new treatment option for these patients. FUNDING: Chipscreen Biosciences.

10.
J Cancer ; 10(4): 1039-1051, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30854110

RESUMO

Cisplatin chemoresistance is a clinical obstacle in the treatment of gastric cancer (GC). Enhanced DNA repair capacity may lead to cisplatin resistance. However, the detailed molecular mechanism of GC cisplatin resistance specifically involving nucleotide excision repair (NER) is not clear. However, the mechanism through which the NER pathway contributes to cisplatin resistance in GC is still unclear. In light of the crucial role of microRNAs (miRNAs) in regulating protein expression and biological behavior, we aimed to analyze the expression and function of miR-192-5p in the NER pathway and its role in cisplatin resistance in GC. Comet assays were performed to measure the amount of DNA damage and repair in the SGC7901 and SGC7901/DDP GC cell lines by observing the tail length. MiRNA expression levels in SGC7901/DDP and SGC7901 cells were detected by microarray. Quantitative real-time PCR (qRT-PCR) was carried out to confirm the expression level of miR-192-5p. Lentiviral vector transfection modifies miR-192-5p levels in SGC7901/DDP and SGC7901 cells. The IC50 values of cisplatin-treated cells were assessed by MTT assays. The protein level was determined by Western blot and immunohistochemistry. With enhanced DNA repair, the expression levels of ERCC3 and ERCC4 in SGC 7901DDP cells increased, while miR-192-5p was significantly downregulated in SGC7901/DDP compared with SGC7901 cells. ERCC3 and ERCC4 were identified as the main targets of miR-192-5p. Forced expression of miR-192-5p in SGC7901/DDP cells significantly inhibited the expression of ERCC3 and ERCC4, making GC cells more sensitive to cisplatin in vitro and in vivo. In contrast, knockdown of miR-192-5p expression in SGC7901 cells increased the expression of ERCC3 and ERCC4, resulting in cisplatin resistance in vitro and in vivo. MiR-192-5p partially reversed GC cisplatin resistance by targeting ERCC3 and ERCC4, which participate in the NER pathway, suggesting that miR-192-5p may be a potential biomarker and therapeutic target for GC cisplatin resistance.

11.
Ann Hematol ; 98(2): 413-422, 2019 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-30374624

RESUMO

Aberrant monocyte chemoattractant protein-1 (MCP-1) and CC chemokine receptor 2 (CCR2) expression in malignant tissues have been reported; however, their role in hematological malignancies prognosis remains little known. The aim of this study was to investigate the prognostic value of MCP-1 and CCR2 expression in patients with diffuse large B cell lymphoma (DLBCL). The study included 221 patients with DLBCL. MCP-1 and CCR2 expression was analyzed by immunohistochemical staining and its correlations with clinicopathologic features and prognosis were evaluated. High expression of MCP-1 or CCR2 was correlated with clinicopathological characteristics, and an adverse prognostic factor for overall survival (OS) and progression-free survival (PFS) of DLBCL patients. Also, significant positive correlation between MCP-1 and CCR2 expression was revealed (r = 0.545, P < 0.001). Patients with high MCP-1 or high CCR2 expression had significantly poorer OS and PFS than those with low MCP-1 or low CCR2 expression (OS: P < 0.001, P < 0.001; PFS: P < 0.001, P < 0.001), respectively, even in the rituximab era, and MCP-1 or CCR2 expression could further identify high-risk patients otherwise classified as low/intermediate risk by the International Prognostic Index (IPI) alone. Furthermore, incorporation of MCP-1 or CCR2 expression into the IPI score could improve prognostic value for OS. This is the first report describing the clinicopathological features and survival outcome according to expression of MCP-1 and CCR2 in DLBCL.


Assuntos
Quimiocina CCL2/sangue , Regulação Neoplásica da Expressão Gênica , Linfoma Difuso de Grandes Células B , Proteínas de Neoplasias/sangue , Receptores CCR2/sangue , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Intervalo Livre de Doença , Feminino , Humanos , Linfoma Difuso de Grandes Células B/sangue , Linfoma Difuso de Grandes Células B/mortalidade , Masculino , Pessoa de Meia-Idade , Taxa de Sobrevida
12.
Oncol Rep ; 41(2): 1131-1139, 2019 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-30535472

RESUMO

The microRNA (miR)­138­5p affects the chemotherapeutic sensitivity of several human cancer types. In the present study, the expression and regulatory mechanisms of miR­138­5p were investigated in the gastric cancer cell line SGC7901 and its cisplatin­resistant derivative SGC7901/DDP. Gene microarray and reverse transcription­quantitative polymerase chain reaction analyses revealed that miR­138­5p was expressed at significantly lower levels in SGC7901/DDP compared with SGC7901 cells. Using computational predictive algorithms, two proteins involved in the nuclear excision repair pathway were identified, excision repair cross­complementing (ERCC)1 and ERCC4, as putative miR­138­5p target genes. Western blot analysis confirmed that ERCC1 and ERCC4 expression levels were inversely proportional to miR­138­5p levels in SGC7901 and SGC7901/DDP cells. Furthermore, ERCC1 and ERCC4 were upregulated in SGC7901 cells expressing miR­138­5p­targeting short hairpin RNA and, conversely, downregulated in SGC7901/DDP cells overexpressing miR­138­5p, confirming that this miRNA regulates ERCC protein levels. Notably, miR­138­5p silencing enhanced the cisplatin resistance of SGC7901 cells, while miR­138­5p overexpression partially reversed the cisplatin resistance of SGC7901/DDP cells. Taken together, these data suggest that miR­138­5p regulates the sensitivity of gastric cancer cells to cisplatin, possibly by modulating expression of the DNA repair proteins ERCC1 and ERCC4.


Assuntos
Antineoplásicos/farmacologia , Cisplatino/farmacologia , Proteínas de Ligação a DNA/genética , Resistencia a Medicamentos Antineoplásicos/genética , Endonucleases/genética , MicroRNAs/metabolismo , Neoplasias Gástricas/tratamento farmacológico , Algoritmos , Antineoplásicos/uso terapêutico , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Proliferação de Células/genética , Cisplatino/uso terapêutico , Biologia Computacional , Reparo do DNA/efeitos dos fármacos , Reparo do DNA/genética , Proteínas de Ligação a DNA/metabolismo , Regulação para Baixo , Endonucleases/metabolismo , Regulação Neoplásica da Expressão Gênica , Técnicas de Silenciamento de Genes , Humanos , MicroRNAs/genética , Análise de Sequência com Séries de Oligonucleotídeos , RNA Interferente Pequeno/metabolismo , Neoplasias Gástricas/genética , Neoplasias Gástricas/patologia , Regulação para Cima
13.
Pathol Res Pract ; 214(11): 1758-1764, 2018 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-30249505

RESUMO

The rs36084323 A > G polymorphism in programmed cell death-1(PD-1) gene has been reported to be associated with cancer risk. However, the results of previous studies were inconsistent. Therefore, we performed a meta-analysis to identify the potential association, by searching the PubMed, EMBASE, Cochrane Library, and the Chinese CNKI, WANFANG and CBM databases. Data were extracted and odds ratios (ORs) with 95% confidence intervals (CIs) were estimated to assess the strength of the association. A total of 10 relevant studies involving 4445 cancer cases and 5126 controls were recruited. Overall, the results indicated that the PD-1 rs36084323 A > G polymorphism was not statistically associated with cancer risk. However, stratified analysis revealed that there was a statistically reduced cancer risk in Asians(G vs. A, OR = 0.89, 95%CI:0.81-0.97, P = 0.008, I2 = 48.8%; GG vs. AA, OR = 0.79, 95% CI:0.66-0.94, P = 0.008, I2 = 48.7%; GG/AG vs. AA, OR = 0.87, 95%CI:0.76-0.98, P = 0.017, I2 = 34.9%; GG vs. AG/AA, OR = 0.85, 95%CI:0.75-0.97, P = 0.027, I2 = 40%) and in the patients with EOC(AG vs. AA, OR = 0.69, 95%CI:0.54-0.90, P = 0.005, I2 = 0%; GG/AG vs. AA, OR = 0.67, 95%CI:0.52-0.85, P = 0.001, I2 = 0). Meta-regression showed that ethnicity (P = 0.029) but not cancer types (P = 0.792), source of controls (P = 0.207) or ample size (P = 0.585) were the sources of heterogeneity. This meta-analysis demonstrates the PD-1 rs36084323 A > G polymorphism is associated with decreased cancer risk in Asian, and suggests it could potentially serve as a biomarker to screen high-risk individuals. Large-scale and well-designed case-control studies are needed to enrich the evidence of this result.


Assuntos
Predisposição Genética para Doença/genética , Neoplasias/genética , Receptor de Morte Celular Programada 1/genética , Grupo com Ancestrais do Continente Asiático/genética , Humanos , Polimorfismo de Nucleotídeo Único
14.
Am J Pathol ; 188(2): 367-377, 2018 02.
Artigo em Inglês | MEDLINE | ID: mdl-29331492

RESUMO

Alcohol consumption likely induces gastric carcinogenesis through deregulation of RNA polymerase (Pol) III genes and oxidative damage. Transcription factor IIB-related factor 1 (BRF1) overexpression alleviates RNA Pol III transcription inhibition through breast cancer susceptibility gene 1 (BRCA1). Myeloperoxidase (MPO) involvement in cancer is induced by alcohol-mediated oxidative damage. BRCA1/2 and MPO play key roles in DNA repair. BRCA1 and BRCA2 exert different roles in homologous recombination repair. By using human gastric cancer (GC) biopsies, we investigated the prognostic value of these proteins upon alcohol induction. In total, high expression of BRF1 (P = 0.010) and positive cell infiltration of MPO (P = 0.004) in tumor tissues as well as positive expression of BRCA1 (P < 0.001) in para-tumor tissues were more frequent in GC patients with hazardous or harmful alcohol consumption habits. BRF1 (P = 0.021), BRCA2 (P < 0.001), and MPO (P = 0.039) were independent prognostic factors for disease-free survival. BRCA1 (P = 0.005) and BRCA2 (P < 0.001) also were identified as independent prognostic factors for overall survival. Furthermore, BRCA2 was an independent unfavorable prognostic factor for disease-free survival and overall survival (P < 0.001) in GC patients who underwent platinum-based adjuvant chemotherapy. BRF1, BRCA1/2, and MPO are DNA repair-related biomarkers, induced by alcohol with prognostic value in GC patients.


Assuntos
Adenocarcinoma/diagnóstico , Alcoolismo/complicações , Biomarcadores Tumorais/metabolismo , Reparo do DNA , Neoplasias Gástricas/diagnóstico , Adenocarcinoma/etiologia , Adenocarcinoma/patologia , Adenocarcinoma/terapia , Adulto , Proteína BRCA2/metabolismo , Biópsia , Quimioterapia Adjuvante , DNA de Neoplasias/genética , Feminino , Humanos , Estimativa de Kaplan-Meier , Masculino , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Peroxidase/metabolismo , Prognóstico , Neoplasias Gástricas/etiologia , Neoplasias Gástricas/patologia , Neoplasias Gástricas/terapia , Fatores Associados à Proteína de Ligação a TATA/metabolismo , Resultado do Tratamento , Ubiquitina-Proteína Ligases/metabolismo
15.
Mol Med Rep ; 17(2): 2952-2956, 2018 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-29257307

RESUMO

Insulin-like growth factor 1 (IGF-1) is reported to inhibit autophagy of human colorectal carcinoma cells (HCT); however, little is known regarding the mechanisms underlying the inhibitory effect of IGF-1 on autophagy in HCT resistant strains. The present study aimed to analyze the inhibitory effect of IGF-1 on the autophagy of HCT resistant strains and its potential underlying mechanisms. The viability and apoptosis of HCT-8 colon cancer cells were analyzed, and expression levels of relevant genes and proteins were investigated using reverse transcription-quantitative polymerase chain reaction and western blot analysis, respectively. Treatment of cells with IGF-1 induced apoptosis. IGF-1 treatment activated protein kinase B (AKT), which may inhibit autophagy via the AKT/mammalian target of rapamycin signaling pathway. Following inhibition of autophagy, drug resistant cells became sensitive to apoptosis induced by 5-fluorouracil.


Assuntos
Autofagia , Neoplasias Colorretais/metabolismo , Fator de Crescimento Insulin-Like I/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Transdução de Sinais , Serina-Treonina Quinases TOR/metabolismo , Antimetabólitos Antineoplásicos/farmacologia , Apoptose/efeitos dos fármacos , Autofagia/efeitos dos fármacos , Linhagem Celular Tumoral , Neoplasias Colorretais/tratamento farmacológico , Resistencia a Medicamentos Antineoplásicos , Fluoruracila/farmacologia , Humanos , Transdução de Sinais/efeitos dos fármacos
16.
Thorac Cancer ; 9(2): 278-283, 2018 02.
Artigo em Inglês | MEDLINE | ID: mdl-29266865

RESUMO

BACKGROUND: The study was conducted to assess differences in overall survival (OS) in patients with non-small cell lung cancer (NSCLC) receiving different treatment modalities of tyrosine kinase inhibitors (TKIs). METHODS: A total of 463 NSCLC patients receiving TKI treatment were included. OS was compared according to treatment timing in all patients, the elderly, and patients positive for EGFR mutations. RESULTS: One hundred and seventy two patients received TKIs as first-line treatment, 220 as second-line, and 67 as third-line. The results between the three groups were not statistically significant: the one, two, and three-year OS rates were: 55.3%, 22.3%, and 11.3% (first-line); 59.6%, 27.8%, and 14.9% (second-line); and 53.8%, 41.3%, and 29.5% (third-line), respectively (P = 0.095). Results between the three groups of elderly patients were also not statistically significant (P = 0.469). The one and two-year OS rates in EGFR mutation-positive patients receiving first-line treatment were 48% and 17.5%, respectively. The one, two, and three-year OS rates of patients receiving second-line treatment were: 54.2%, 30.3%, and 20.2%, respectively. There were no statistically significant differences between the groups with EGFR mutations receiving first-line or second-line treatment. Thirteen EGFR mutation-positive patients received third-line TKI treatment for a median duration of 7 months. Their one and two-year OS rates were 69.8% and 58.2%, respectively, which were higher than in the other two groups (P = 0.015). CONCLUSION: Three lines of TKI therapy can prolong survival in NSCLC patients. Elderly patients can benefit from TKI therapy. EGFR mutation-positive patients can benefit from second-line or third-line TKI therapy.


Assuntos
Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Receptores ErbB/genética , Inibidores de Proteínas Quinases/administração & dosagem , Idoso , Idoso de 80 Anos ou mais , Carcinoma Pulmonar de Células não Pequenas/epidemiologia , Carcinoma Pulmonar de Células não Pequenas/genética , Carcinoma Pulmonar de Células não Pequenas/patologia , Intervalo Livre de Doença , Humanos , Pessoa de Meia-Idade , Mutação , Estadiamento de Neoplasias , Inibidores de Proteínas Quinases/efeitos adversos , Estudos Retrospectivos , Resultado do Tratamento
17.
Oncotarget ; 8(31): 51190-51199, 2017 Aug 01.
Artigo em Inglês | MEDLINE | ID: mdl-28881640

RESUMO

We examined microRNA-200c (miR-200c) expression in tumor tissues and plasma of patients with advanced gastric cancer and correlated miR-200c expression with treatment efficacy of platinum chemotherapy and patient prognosis. Tumor tissues were collected from 51 patients with advanced gastric cancer who received platinum-containing chemotherapies. The plasma was collected from the same group of patients and 51 subjects with chronic superficial gastritis. Quantitative RT-PCR was used to evaluate miR-200c expression, and its correlation with treatment efficacy and patient prognosis was analyzed. The results showed that the miR-200c expression in gastric cancer tissues and in plasma were significantly lower than tumor-adjacent tissues and in patients with chronic superficial gastritis (both p <0.05). No significant correlation was found between miR-200c expression in tumors or plasma and clinical characteristics. Patients with higher miR-200c expression had better treatment outcomes with platinum chemotherapy and longer progression-free survival and overall survival than patients with lower miR-200c expression. Receiver-operating characteristic curve analysis showed that miR-200c expression in gastric cancer tissues and plasma distinguished patients' treatment outcomes. Multivariate analyses confirmed that over expression of miR-200c both in gastric cancer tissue and plasma is associated with longer progression-free survival and overall survival. Taken together, our study indicated that miR-200c expression in gastric cancer tissues and plasma of patients with advanced gastric cancer is associated with better treatment efficacy and prognosis with platinum chemotherapy, suggesting that expression of miR-200c may be predictive for chemotherapy and prognosis in advanced gastric cancer patients.

18.
World J Gastroenterol ; 23(7): 1189-1202, 2017 Feb 21.
Artigo em Inglês | MEDLINE | ID: mdl-28275299

RESUMO

AIM: To explore novel therapeutic target of cisplatin resistance in human gastric cancer. METHODS: The sensitivity of SGC7901 cells and cisplatin-resistant SGC7901 cells (SGC7901/DDP) for cisplatin were detected by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl-tetrazolium bromide (MTT) assay. High-quality total RNA which isolated from SGC7901/DDP cells and SGC7901 cells were used for mRNA microarray analysis. Results were analyzed bioinformatically to predict their roles in the development of cisplatin resistance and the expression of 13 dysregulated mRNAs we selected were validated by quantitative real-time polymerase chain reaction (qRT-PCR). RESULTS: SGC7901/DDP cells highly resistant to cisplatin demonstrated by MTT assay. A total of 1308 mRNAs (578 upregulated and 730 downregulated) were differentially expressed (fold change ≥ 2 and P-value < 0.05) in the SGC7901/DDP cells compared with SGC7901 cells. The expression of mRNAs detected by qRT-PCR were consistent with the microarray results. Gene Ontology, Kyoto Encyclopedia of Genes and Genomes pathway and protein-protein interaction analysis demonstrated that the differentially expressed mRNAs were enriched in PI3K-Akt, Notch, MAPK, ErbB, Jak-STAT, NF-kappaB signaling pathways which may be involved in cisplatin resistance. Several genes such as PDE3B, VEGFC, IGFBP3, TLR4, HIPK2 and EGF may associated with drug resistance of gastric cancer cells to cisplatin. CONCLUSION: Exploration of those altered mRNAs may provide more promising strategy in diagnosis and therapy for gastric cancer with cisplatin resistance.


Assuntos
Antineoplásicos/farmacologia , Cisplatino/farmacologia , Regulação Neoplásica da Expressão Gênica , Neoplasias Gástricas/genética , Linhagem Celular Tumoral , Sobrevivência Celular , Biologia Computacional , Resistência a Múltiplos Medicamentos/genética , Resistencia a Medicamentos Antineoplásicos , Perfilação da Expressão Gênica , Humanos , NF-kappa B/metabolismo , Análise de Sequência com Séries de Oligonucleotídeos , Fosfatidilinositol 3-Quinases/metabolismo , RNA Mensageiro/metabolismo , Neoplasias Gástricas/tratamento farmacológico
19.
Oncotarget ; 7(35): 57301-57309, 2016 Aug 30.
Artigo em Inglês | MEDLINE | ID: mdl-27359058

RESUMO

The international CONFIRM study showed that fulvestrant 500 mg improved progression-free survival (PFS) vs fulvestrant 250 mg in postmenopausal women with estrogen receptor (ER)-positive locally advanced/metastatic breast cancer (LA/MBC). In this randomized, double-blind study, postmenopausal Chinese women with ER-positive LA/MBC and progression after endocrine therapy received fulvestrant 500 mg (days 0, 14, 28, and every 28 days thereafter) or fulvestrant 250 mg (every 28 days). Consistency with the international study was assumed if the hazard ratio (HR) for comparison of PFS (primary endpoint) was < 1 (stratified log-rank test). The study was not powered to assess between-group differences.In total, 221 patients were randomized (fulvestrant 500 mg: n = 111; fulvestrant 250 mg: n = 110). Baseline characteristics were balanced. Median PFS was 8.0 months with fulvestrant 500 mg vs 4.0 months with 250 mg (HR = 0.75; 95% confidence interval [CI] 0.54-1.03; P = 0.078). PFS (HR; 95% CI) favored fulvestrant 500 mg in post-antiestrogen (0.86; 0.54-1.37) and post-aromatase inhibitor (0.65; 0.42-1.03) settings. No new safety considerations were observed. These results are consistent with the international CONFIRM study, supporting the superior clinical benefit of fulvestrant 500 mg in women with ER-positive LA/MBC experiencing progression following prior endocrine therapy.


Assuntos
Antineoplásicos Hormonais/administração & dosagem , Neoplasias da Mama/tratamento farmacológico , Esquema de Medicação , Estradiol/análogos & derivados , Receptor alfa de Estrogênio/metabolismo , Adulto , Idoso , Idoso de 80 Anos ou mais , Inibidores da Aromatase/administração & dosagem , Neoplasias da Mama/metabolismo , China , Intervalo Livre de Doença , Método Duplo-Cego , Estradiol/administração & dosagem , Antagonistas de Estrogênios/administração & dosagem , Moduladores de Receptor Estrogênico/administração & dosagem , Feminino , Fulvestranto , Humanos , Pessoa de Meia-Idade , Segurança do Paciente , Pós-Menopausa , Modelos de Riscos Proporcionais
20.
Am J Cancer Res ; 6(2): 226-37, 2016.
Artigo em Inglês | MEDLINE | ID: mdl-27186398

RESUMO

Cholangiocarcinoma (CCA), the most common biliary tract malignancy, is arising from the bile duct epithelium with the global significantly increased morbidity and mortality. Here, we showed the effect of guggulsterone, a steroid found in the resin of the guggul plant, on human HuCC-T1 and RBE CCA cells. Exposure to various concentrations of guggulsterone for multiple action time resulted in significant apoptosis in the CCA cells via activating both extrinsic and intrinsic pathways. Furthermore, we demonstrated that the apoptosis of CCA cells was induced by Reactive oxygen species (ROS) mediated JNK signaling pathway. Consistently, inhibition of JNK activity, overexpression of JBD, its binding protein or reduction of ROS by overexpression of catalase, all decreased apoptotic cells. Our results also revealed that guggulsterone-induced apoptosis was coupled with endoplasmic reticulum stress (ERS) in CHOP-dependent pathway. Downregulation of CHOP instead of other ERS markers could inhibit CCA cell apoptosis. Taken together, our results showed that guggulsterone could induce apoptosis of human CCA cells through ROS/JNK signaling pathway, indicating that guggulsterone could be important for the clinical therapy of CCA.

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