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1.
J Thorac Oncol ; 2021 Apr 26.
Artigo em Inglês | MEDLINE | ID: mdl-33915252

RESUMO

INTRODUCTION: ZL-2306-005 is a randomized, double-blind, multicenter phase 3 study evaluating the efficacy and safety of niraparib, a poly(ADP-ribose) polymerase inhibitor, as first-line maintenance therapy in Chinese patients with platinum-responsive, extensive-stage small cell lung cancer (ES-SCLC). METHODS: Patients with complete/partial response (CR/PR) to standardized, platinum-based first-line chemotherapy were randomized 2:1 to receive niraparib or placebo (300 mg [baseline body weight ≥77 kg, platelet count ≥150,000/µL] or 200 mg) once daily until progression or unacceptable toxicity. Primary endpoints were progression-free survival (PFS) (blinded independent central review, BICR) and overall survival (OS) (sample size planned: 591 patients). Secondary endpoints included investigator-assessed PFS and safety. RESULTS: ZL-2306-005 was terminated early due to ES-SCLC treatment landscape changes (data cut-off: 20 Mar 2020). During July 2018-February 2020, 185 of 272 patients screened were randomized (niraparib: n=125 [CR=1, PR=124]; placebo: n=60 [CR=1, PR=59]). Median (95% confidence interval [CI]) PFS (BICR) was 1.54 months (1.41-2.69, niraparib) and 1.36 months (1.31-1.48, placebo); hazard ratio [HR]=0.66 (95% CI: 0.46-0.95; p=0.0242). Median OS was 9.92 months (9.33-13.54, niraparib) and 11.43 months (9.53-not estimable, placebo); HR=1.03 (95% CI: 0.62-1.73; p=0.9052). Median investigator-assessed PFS was 1.48 months (1.41-2.56, niraparib) and 1.41 months (1.31-2.00, placebo); HR=0.88 (95% CI: 0.61-1.26; p=0.4653). Grade ≥3 adverse events occurred in 34.4% (niraparib) and 25.0% (placebo) of patients. CONCLUSIONS: ZL-2306-005 did not reach primary endpoints. However, niraparib as maintenance therapy modestly improved PFS in patients with platinum-responsive ES-SCLC, with acceptable tolerability profile and no new safety signal.

2.
Cancer Biol Med ; 2021 Mar 12.
Artigo em Inglês | MEDLINE | ID: mdl-33710815

RESUMO

OBJECTIVE: This phase 3 study aimed to test equivalence in efficacy and safety for QL1101, a bevacizumab analogue in Chinese patients with untreated locally advanced non-squamous non-small cell lung cancer (NSCLC). METHODS: Eligible patients were randomly assigned 1:1 to receive carboplatin and paclitaxel in combination with either QL1101 or bevacizumab, 15 mg/kg every 3-week for 6 cycles. This was followed by maintenance treatment with single agent QL1101 every 3-week. The primary end-point was objective response rate (ORR), with secondary end-points being progression-free survival (PFS), overall survival (OS), disease control rate (DCR), and adverse events (AEs). RESULTS: Of 675 patients, 535 eligible patients were randomized to the QL1101 group (n = 269) and bevacizumab group (n = 266). ORRs were 52.8% and 56.8%, respectively, for the QL1101 and bevacizumab groups, with an ORR hazard ratio 0.93 (95% confidence interval: 0.8-0131.1). The PFS, OS, DCR, and AEs were comparable between the 2 groups, which remained the same after stratification according to epidermal growth factor receptor mutation or smoking history. CONCLUSIONS: QL1101 showed similar efficacy and safety profiles as compared to bevacizumab among Chinese patients with untreated locally advanced non-squamous NSCLC.

3.
Target Oncol ; 16(2): 165-176, 2021 03.
Artigo em Inglês | MEDLINE | ID: mdl-33544337

RESUMO

BACKGROUND: In the global FLAURA study, first-line osimertinib, a third-generation irreversible tyrosine kinase inhibitor (TKI) of epidermal growth factor receptor (EGFR), significantly improved progression-free survival (PFS) and overall survival (OS) versus comparator EGFR TKIs in patients with EGFR mutation-positive (EGFRm) advanced non-small-cell lung cancer (NSCLC). OBJECTIVE: The FLAURA China study assessed first-line osimertinib in Chinese patients with EGFRm advanced NSCLC (NCT02296125). METHODS: FLAURA China was a double-blind, randomized, phase III study. Adults from mainland China with previously untreated EGFRm (Exon 19 deletion or L858R) advanced NSCLC were enrolled in the global study or a China-only study under the same protocol; 136 patients were randomized to osimertinib (80 mg once daily [od]; n = 71) or comparator EGFR TKI (gefitinib or erlotinib; all sites selected gefitinib 250 mg od; n = 65). Patients were randomized and allocated to treatment groups by a central computer system. Treatment continued until disease progression, unacceptable toxicity, or withdrawal of consent. The primary endpoint was investigator-assessed PFS; OS was a secondary endpoint. RESULTS: All 136 randomized patients were analyzed. Osimertinib extended median PFS by 8.0 months versus comparator EGFR TKI (17.8 vs. 9.8 months; hazard ratio [HR] 0.56; 95% confidence interval [CI] 0.37-0.85). Median OS was 33.1 months in the osimertinib group versus 25.7 months in the comparator group (HR 0.85; 95% CI 0.56-1.29). At 3 years, 20% of patients on osimertinib and 8% on the comparator remained on randomized treatment. Grade 3 or higher adverse events (AEs) were reported in 54 and 28% of patients in the osimertinib and comparator groups, respectively, driven by increased local reporting of laboratory- and disease-related AEs. No new safety signals were identified. CONCLUSIONS: First-line osimertinib treatment resulted in a clinically meaningful PFS and OS benefit versus comparator EGFR TKI in Chinese patients with EGFRm advanced NSCLC. Safety data were consistent with the known safety profile of osimertinib. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov NCT02296125, registered 20 November 2014.

4.
Genome ; 2021 Feb 04.
Artigo em Inglês | MEDLINE | ID: mdl-33539259

RESUMO

Spinach (Spinacia oleracea L.) is commonly considered a dioecious plant with heterogametic (XY) and homogametic (XX) sex chromosomes. The characteristic is also utilized for the production of spinach hybrid seeds. However, the molecular mechanisms of sex determination in spinach are still unclear because of a lack of genomic and transcriptomic information. In this study, RNA-sequencing (RNA-seq) was performed in male and female inflorescences to provide insight into the molecular basis of sex determination in spinach. Comparative transcriptome analyses showed that 2,278 differentially expressed genes (DEGs) were identified between male and female inflorescences. A high correlation between the RNA-Seq and qRT-PCR validation for DEGs was observed. Among these, 182 DEGs were annotated to transcription factors including the MYB family protein, bHLH family, and MADS family, suggesting these factors might play a vital role in sex determination. Moreover, 26 DEGs related to flower development, including nine ABCE class genes, were detected. Expression analyses of hormone pathways showed that brassinosteroids may be key hormones related to sex determination in spinach. Overall, this study provides a large amount of DEGs related to sexual expression and lays a foundation for unraveling the regulatory mechanism of sex determination in spinach.

5.
Theor Appl Genet ; 134(5): 1319-1328, 2021 May.
Artigo em Inglês | MEDLINE | ID: mdl-33515081

RESUMO

KEY MESSAGE: The Fs gene, which controls spinach fruit spines, was fine mapped to a 0.27 Mb interval encompassing four genes on chromosome 3. There are two types of fruit of spinach (Spinacia oleracea L.), spiny and spineless, which are visually distinguishable by the spines of fruit coat. In spinach breeding, the fruit characteristic is an important agronomic trait that have impacts on "seed" treatment and mechanized sowing. However, the gene(s) controlling the fruit spiny trait have not been characterized and the genetic mechanism of this trait remained unclear. The objectives of the study were to fine map the gene controlling fruit spines and develop molecular markers for marker-assisted selection purpose. Genetic analysis of the spiny trait in segregating populations indicated that fruit spines were controlled by a single dominant gene, designated as Fs. Using a super-BSA method and recombinants analysis in a BC1 population, Fs was mapped to a 1.9-Mb interval on chromosome 3. The Fs gene was further mapped to a 0.27-Mb interval using a recombinant inbred line (RIL) population with 120 lines. From this 0.27 Mb region, four candidate genes were identified in the reference genome. The structure and expression of the four genes were compared between the spiny and spineless parents. A co-dominant marker YC-15 was found to be co-segregating with the fruit spines trait, which produced a 129-bp fragment specific to spiny trait and a 108-bp fragment for spineless fruit. This marker can predict spiny trait with a 94.8% accuracy rate when tested with 100 diverse germplasm, suggesting that this marker would be valuable for marker-assisted selection in spinach breeding.

6.
Ther Adv Med Oncol ; 12: 1758835920965849, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-33281949

RESUMO

Background: Carboxyamidotriazole (CAI), a calcium channel blocker, inhibits tumor cell proliferation, metastasis, and angiogenesis. This trial aimed to determine whether CAI combined with conventional chemotherapy could prolong progression-free survival (PFS) in non-small cell lung cancer (NSCLC) patients. Methods: Patients were assigned into groups (3:1 ratio) to receive either chemotherapy + CAI or chemotherapy alone. Cisplatin (25 mg/m2) was administered by intravenous infusion on days 1, 2, and 3, and vinorelbine (25 mg/m2) on days 1 and 8 of each 3-week cycle for four cycles. CAI was administered at 100 mg daily with concomitant chemotherapy; this treatment was continued after chemotherapy was ceased until serious toxicity or disease progression had occurred. PFS was the primary endpoint, and the secondary endpoints were objective response rate (ORR), disease control rate, overall survival (OS), and quality of life. Results: In total, 495 patients were enrolled in the trial: 378 in the chemotherapy + CAI group and 117 in the chemotherapy + placebo group. PFS was significantly greater in the chemotherapy + CAI [median, 134 days; 95% confidence interval (CI) 127-139] than in the chemotherapy + placebo (median, 98 days; 95% CI: 88-125) group, with a hazard ratio of 0.690 (95% CI: 0.539-0.883; p = 0.003). There was no difference in the OS rates of both groups. The ORR was greater in the chemotherapy + CAI group than in the chemotherapy + placebo group (34.6% versus 25.0%, p = 0.042). Adverse events of ⩾grade 3 occurred more frequently in the CAI group [256 (68.1%) versus 64 (55.2%); p = 0.014]. Conclusion: CAI + platinum-based chemotherapy prolonged PFS and could be a useful therapeutic option to treat NSCLC. Clinical Trial Registration: chinadrugtrials.org.cn identifier: CTR20160395.

7.
Chin Clin Oncol ; 9(5): 68, 2020 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-33161724

RESUMO

BACKGROUND: The goal of this study was to evaluate aprepitant usage in the context of routine clinical practice with dose/regimens at the discretion of prescribers for chemotherapy-induced nausea and vomiting (CINV) treatments. METHODS: In this single arm, multicenter prospective study 1,000 patients with solid malignancies were enrolled across 21 centers in China. The primary endpoint was the rate of adverse events (AEs), including drug related AEs and serious AEs (SAEs). Secondary efficacy endpoints included the proportion of patients achieving complete response (CR; no vomiting, no nausea, and no use of rescue medication) within 120 h after highly emetogenic chemotherapy, the rates of no nausea and no vomiting, as well as quality of life (QoL). Multivariable logistic regression analysis was carried out to determine factors associated with the overall (0-120 h), acute (0-24 h) and delayed (25-120 h) CR. RESULTS: Of the 1,000 highly emetogenic chemotherapy treated patients enrolled in the study ≥1 AE, ≥1 drug related AE, ≥1 SAE and drug related SAE rates in 998 patients were 45.9%, 2.5%, 4.0% and 0.1%, respectively. Approximately half of the patients (455/990, 46.0%) received aprepitant as part of a 3-drug anti-CINV regimen consistent with prescribing guidelines. The overall CR (0 to 120 h) for anti-emetic drug use was 41.0%, with an acute CR of 66.0% and a delayed CR of 46.5%. The rates of no vomiting and no nausea after solely aprepitant anti-emetic therapy from 0 to 120 h were 70.9% and 43.0%, for dual anti-emetic therapy 86.9% and 64.6%, and for triple therapy 86.4% and 69.5%, respectively. Multivariate regression analysis revealed that triple anti-emetic therapy (P=0.038), male gender (P<0.001) and a history of chemotherapy (P=0.016) were significantly associated with the overall acute CR. CONCLUSIONS: Especially as a combination treatment, aprepitant is safe and efficient for preventing CINV in patients receiving highly emetogenic chemotherapy.

8.
Am J Cancer Res ; 10(9): 3037-3046, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-33042632

RESUMO

Gastric cancer (GC) is the second most common cancer in China. The ToGA study showed that trastuzumab in combination with fluoropyrimidine plus cisplatin prolonged overall survival (OS) in patients with human epidermal growth factor receptor 2 (HER2)-positive advanced GC (AGC). However, some patients may not be able to receive this regimen. We conducted a clinical study to evaluate the efficacy and safety of trastuzumab in combination with docetaxel+capecitabine (DX) in patients with HER2-positive AGC. This phase II, multi-center, open-label, single arm study enrolled patients with HER2-positive AGC who had not received prior treatment for metastatic disease. Patients were treated with a regimen of trastuzumab (8 mg/kg loading dose followed by 6 mg/kg, day 1), capecitabine (1000 mg/m2 twice daily, days 1-14) and docetaxel (60 mg/m2, day 1 for 6 cycles) every 3 weeks. The primary endpoint was progression-free survival (PFS) and the secondary endpoints were objective response rate (ORR), OS and safety profiles. Sixty-seven patients with AGC were enrolled from 14 centers. 64 were included in the full analysis set (FAS). The median PFS was 8.1 months (95% confidence interval [CI]: 5.6-12.8) and the median OS was 20.9 months (95% CI: 15.1-33.0). Response was evaluated in 59 patients. The ORR was 67.8%. The most common adverse events of Grade ≥3 were neutropenia, leukopenia, hand-foot syndrome, febrile neutropenia and anemia. We concluded that combination treatment with trastuzumab and DX was well-tolerated and highly effective in patients with HER2-positive AGC, and may offer an alternative to current treatments.

9.
Front Oncol ; 10: 1568, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-33042801

RESUMO

Objective: This study investigated survival in selected Chinese patients with advanced lung adenocarcinoma who received initial chemotherapy with pemetrexed. We also explored the relationship between genetic biomarkers and pemetrexed efficacy. Methods: We retrospectively collected patients (n = 1,047) enrolled in the Chinese Patient Assistance Program from multiple centers who received pemetrexed alone or combined with platinum as initial chemotherapy and continued pemetrexed maintenance therapy for advanced lung adenocarcinoma from November 2014 to June 2017. The outcomes were duration of treatment (DOT) and overall survival (OS). Clinical features were analyzed for their influence on the treatment effect and prognosis. Next-generation sequencing (NGS) was performed to identify genetic biomarkers associated with the efficacy of pemetrexed. Results: The median DOT was 9.1 months (95% CI: 8.5-9.8), and the median OS was 26.2 months (95% CI: 24.2-28.1). OS was positively correlated with DOT (r = 0.403, P < 0.001). Multivariable analysis showed that smoking status and Eastern Cooperative Oncology Group (ECOG) performance status (PS) were independently associated with DOT; smoking status, ECOG PS, targeted therapy, and EGFR/ALK/ROS1 status were independently associated with OS. NGS in 22 patients with available samples showed genes with high mutation rates were: TP53 (54.5%), EGFR (50.0%), MYC (18.2%), and PIK3CA (13.6%). When grouped based on progression-free survival (PFS) reported in the PARAMOUNT study, the DOT > 6.9 months set was associated with PIK3CA, ALK, BRINP3, CDKN2A, CSMD3, EPHA3, KRAS, and RB1 mutations, while ERBB2 mutation was observed only in the DOT ≤ 6.9 months set. Conclusion: This study shows that initial chemotherapy with pemetrexed is an effective regimen for advanced lung adenocarcinoma in selected Chinese patients. There is no specific genetic profile predicting the benefit of pemetrexed found by NGS. Biomarkers predicting the efficacy of pemetrexed need further exploration.

10.
Lancet Oncol ; 21(6): 832-842, 2020 06.
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.


Assuntos
Anticorpos Monoclonais Humanizados/administração & dosagem , Antineoplásicos Imunológicos/administração & dosagem , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Docetaxel/administração & dosagem , Neoplasias Esofágicas/tratamento farmacológico , Carcinoma de Células Escamosas do Esôfago/tratamento farmacológico , Irinotecano/administração & dosagem , Adolescente , Adulto , Idoso , Anticorpos Monoclonais Humanizados/efeitos adversos , Antineoplásicos Imunológicos/efeitos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , China , Progressão da Doença , Docetaxel/efeitos adversos , Neoplasias Esofágicas/imunologia , Neoplasias Esofágicas/mortalidade , Neoplasias Esofágicas/patologia , Carcinoma de Células Escamosas do Esôfago/imunologia , Carcinoma de Células Escamosas do Esôfago/mortalidade , Carcinoma de Células Escamosas do Esôfago/secundário , Feminino , Humanos , Irinotecano/efeitos adversos , Masculino , Pessoa de Meia-Idade , Receptor de Morte Celular Programada 1/antagonistas & inibidores , Receptor de Morte Celular Programada 1/imunologia , Intervalo Livre de Progressão , Transdução de Sinais , Fatores de Tempo , Adulto Jovem
11.
Oncol Rep ; 43(2): 662-670, 2020 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-31894344

RESUMO

Cullin 4A (CUL4A) is a member of the cullin family of proteins and has been demonstrated to be abnormally expressed in various types of malignancies. However, the function of CUL4A in metastasis of lung adenocarcinoma to the bone has rarely been reported. The aim of present of the study was to explore the biological functions and potential underlying molecular mechanisms of CUL4A in lung adenocarcinoma, highlighting a novel therapeutic target for the diagnosis and treatment of patients with lung adenocarcinoma. A549­CUL4A, H1299­CUL4A and H460­shCUL4A cells were created using lentiviral infection. The efficiency of knockdown or overexpression was assessed using reverse transcription­quantitative PCR and western blotting. The effects of CUL4A on proliferation, migration and invasion of lung adenocarcinoma cells in vitro and metastasis to the bone in vivo were determined using an MTT assay, colony formation assay, wound­healing assay, Transwell assay and a mouse model of bone metastasis. The relationship between CUL4A and the EMT­activator zinc finger E­box binding homeobox 1 (ZEB1) were detected by western blotting. The results showed that overexpression of CUL4A in lung adenocarcinoma cells increased proliferation, migration and invasion, and increased metastasis of A549 to the bones in vivo. Silencing of CUL4A expression in lung adenocarcinoma cells reduced proliferation, migration and invasion in vitro. Mechanistically, CUL4A transcriptionally upregulated expression of ZEB1 which resulted in epithelial­mesenchymal transition, which in turn promoted metastasis of lung adenocarcinoma to the bones. Taken together, these results suggest that CUL4A may serve an important regulatory role in the development of metastasis of lung adenocarcinoma to the bone.


Assuntos
Adenocarcinoma de Pulmão/patologia , Neoplasias Ósseas/patologia , Neoplasias Ósseas/secundário , Proteínas Culina/genética , Proteínas Culina/metabolismo , Neoplasias Pulmonares/patologia , Homeobox 1 de Ligação a E-box em Dedo de Zinco/genética , Células A549 , Adenocarcinoma de Pulmão/genética , Adenocarcinoma de Pulmão/metabolismo , Animais , Neoplasias Ósseas/genética , Neoplasias Ósseas/metabolismo , Linhagem Celular Tumoral , Movimento Celular , Proliferação de Células , Transição Epitelial-Mesenquimal , Feminino , Regulação Neoplásica da Expressão Gênica , Humanos , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/metabolismo , Camundongos , Transplante de Neoplasias , Regulação para Cima
12.
J Assist Reprod Genet ; 37(2): 395-403, 2020 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-31938932

RESUMO

PURPOSE: To investigate whether exosomes derived from human umbilical cord mesenchymal stem cells (hucMSC-derived exosomes) can repair injured endometrial epithelial cells (EECs). METHODS: HucMSC-derived exosomes and mouse primary EECs were isolated and purified. EECs were exposed to oxygen and glucose deprivation for 2 h followed by reoxygenation to mimic injury. After oxygen and glucose deprivation/reoxygenation (OGD/R), hucMSC-derived exosomes were added to the EEC culture medium. After 24 h of co-treatment, cell viability and cell death were tested by 3-(4,5-dimethylthiazol-2-yl)-5-(3-carboxymethoxyphenyl)-2-(4-sulfophenyl)-2H-tetrazolium assay and lactate dehydrogenase (LDH) assay, respectively. The expression of proinflammatory cytokines was tested by real-time PCR, enzyme-linked immunosorbent assay (ELISA), and Western blot to investigate the potential mechanism. RESULTS: Compared with the control group, 5, 10, and 15 µg/mL of hucMSC-derived exosomes significantly attenuated cell viability decrease and inhibited LDH release of injured EECs, but 1 µg/mL of hucMSC-derived exosomes had no effect on either cell viability or LDH release. Real-time PCR and ELISA analysis revealed that 10 µg/mL of hucMSC-derived exosomes significantly inhibited the release of interleukin-6 (IL-6) and interleukin-1 beta (IL-1ß) and increased tumor necrosis factor alpha (TNFA) in injured EECs. In addition, 10 µg/mL of hucMSC-derived exosomes significantly inhibited toll-like receptor 4 (TLR4) and v-rel reticuloendotheliosis viral oncogene homolog A (RelA) expression in injured EECs. CONCLUSIONS: In OGD/R-induced injured EECs, hucMSC-derived exosomes efficiently improved the cell viability, reduced cell death, and exhibited anti-inflammatory properties against OGD/R.

13.
J BUON ; 24(2): 591-598, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31128011

RESUMO

PURPOSE: MicroRNAs are involved in the occurrence and progression of tumors. Previous studies have confirmed that microRNA-203 serves as an oncogene. The specific role of microRNA-203 in non-small cell lung cancer (NSCLC) is rarely reported. This study aimed to explore the regulatory effect of microRNA-203 on NSCLC and its underlying mechanism. METHODS: MicroRNA-203 expression in 96 pairs of NSCLC tissues and paracancer tissues was detected by quantitative real-time polymerase chain reaction (qRT-PCR). Correlation between microRNA-203 expression and prognosis of NSCLC was further analyzed. Proliferative, migratory and invasive abilities of NSCLC cells after transfection with si-microRNA-203 or si-negative control (NC) were assessed by cell counting kit-8 (CCK-8), 5-Ethynyl-2'-deoxyuridine (EdU), colony formation and Transwell assay, respectively. Rescue experiments were conducted to investigate the interaction between microRNA-203 and survivin in regulating NSCLC progression. RESULTS: MicroRNA-203 was highly expressed in NSCLC tissues than in paracancer tissues. Correlation analyses showed that microRNA-203 expression was positively correlated to tumor stage, lymph node metastasis and distant metastasis, whereas it was not correlated to age and sex of NSCLC patients. MicroRNA-203 knockdown inhibited proliferative, migratory and invasive abilities of NSCLC cells. Rescue experiments confirmed that microRNA-203 promotes the progression of NSCLC via targeting survivin. CONCLUSIONS: MicroRNA-203 is highly expressed in NSCLC, and is closely related to tumor stage, lymph node metastasis, distant metastasis and poor prognosis of NSCLC patients. It is concluded that microRNA-203 promotes the progression of NSCLC via regulating survivin expression.


Assuntos
Biomarcadores Tumorais/genética , Carcinoma Pulmonar de Células não Pequenas/genética , MicroRNAs/genética , Survivina/genética , Idoso , Apoptose/genética , Carcinoma Pulmonar de Células não Pequenas/patologia , Movimento Celular/genética , Proliferação de Células/genética , Progressão da Doença , Intervalo Livre de Doença , Feminino , Regulação Neoplásica da Expressão Gênica , Humanos , Metástase Linfática/genética , Metástase Linfática/patologia , Masculino , Pessoa de Meia-Idade , Invasividade Neoplásica/genética , Invasividade Neoplásica/patologia , Prognóstico
14.
Oncol Lett ; 17(5): 4701-4709, 2019 May.
Artigo em Inglês | MEDLINE | ID: mdl-30988825

RESUMO

The majority of previous studies of lobaplatin in small cell lung cancer (SCLC) are small phase I-II studies. The present study aimed to verify the non-inferiority (in terms of efficacy) of lobaplatin plus etoposide (EL) vs. cisplatin plus etoposide (EP) in patients with previously untreated extensive-stage SCLC (ES-SCLC). This phase III non-inferiority randomized clinical trial enrolled patients at 17 sites between September 2010 and May 2013. Patients were randomized to EL (30 mg/m2 lobaplatin on day 1 and 100 mg/m2 etoposide on days 1-3, for 21-day cycles) or EP (80 mg/m2 cisplatin on day 1 and 100 mg/m2 etoposide on days 1-3, for 21-day cycles). The primary endpoint was progression-free survival (PFS). Secondary endpoints included overall survival (OS), objective response rate, disease control rate (DCR), toxicity and quality of life (QoL). A total of 234 patients were randomized to the EL (n=122) and EP (n=112) treatment groups. The median PFS, median OS and DCR were 5.1 vs. 5.3 months (P=0.786), 10.6 vs. 9.7 months (P=0.701) and 85.5 vs. 86.7% (P=0.848) in the EL vs. EP groups, respectively. Patients in the EL group had significantly lower frequencies of nephrotoxicity (2.5 vs. 11.7%; P=0.008), nausea (22.3 vs. 40.5%; P=0.003) and vomiting (14.1 vs. 35.1%; P<0.001) than those in the EP group. Overall, EL was not inferior to EP in terms of PFS and OS. The tolerance and QoL of the EL regimen were better than those of the EP regimen. EL is thus an alternative choice for the first-line treatment of ES-SCLC.

15.
Oncol Rep ; 41(4): 2379-2388, 2019 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-30816507

RESUMO

Lung cancer is the most common malignant tumor in China. It often metastasizes to bone, thereby significantly shortening the lives of patients, and reducing their quality of life. However, the efficacy of treatment for bone metastasis of lung cancer at this stage is very limited. The development and clinical application of molecular­targeted drugs for the effective targeted therapy of bone metastasis of lung cancer are urgently required. The growth differentiation factor 15 (GDF15) gene which may be associated with bone metastasis of lung cancer, was screened out by whole­genome sequencing. In the present study, we used a recombinant GDF15 lentivirus technique to upregulate the expression of GDF15 in lung adenocarcinoma A549 cells, and the results revealed that GDF15 could inhibit the proliferation, migration and invasion, while promoting apoptosis of A549 cells. In addition, GDF15 significantly decreased the number and sites of lung metastases and bone metastases in vivo compared to the control group. Finally, it was revealed that Smad2 and phospho­Smad2 protein expression was lower in the GDF15­overexpressing A549 cells. This result indicated that the tumor suppressive effect of GDF15 may be related to the TGF­ß/Smad signaling pathway, although more studies are still required for confirmation. In summary, GDF15 inhibited the growth and bone metastasis of lung adenocarcinoma A549 cells, and this effect may be achieved through the TGF­ß/Smad signaling pathway.


Assuntos
Adenocarcinoma de Pulmão/patologia , Neoplasias Ósseas/patologia , Fator 15 de Diferenciação de Crescimento/metabolismo , Neoplasias Pulmonares/patologia , Células A549 , Adenocarcinoma de Pulmão/secundário , Animais , Neoplasias Ósseas/secundário , Movimento Celular , Proliferação de Células , Feminino , Humanos , Camundongos , Proteínas Recombinantes/metabolismo , Transdução de Sinais , Regulação para Cima , Ensaios Antitumorais Modelo de Xenoenxerto
16.
Ther Clin Risk Manag ; 15: 293-302, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30858709

RESUMO

Background: Given the increasing use of immune checkpoint inhibitors (ICIs), a concomitant rise in adverse events is inevitable. In a recent Phase III trial of ICIs versus placebo, we found the staggering difference of incidence of fatal adverse events (FAEs). Hence, we should determine the risk of FAEs in ICIs. Objective: To address the risks of FAEs associated with each ICI regimen, we performed a systematic review and meta-analysis of clinical trials with the Food and Drug Administration-approved ICI regimens in patients with advanced solid tumors. Methods: Literature searching was based on PubMed before April 15, 2018. The numbers of FAEs in both study group and placebo group were collected. We assessed the risk of fatal adverse reactions associated with ICIs on Pooled Peto OR and associated 95% CI. Results: Twelve trials were identified. OR value of FADs in all ICIs was 2.32 (95% CI: 1.33, 4.05; P=0.003). The incidence of FAE in ICI in all included studies were up to 3.2%. OR value of clinical trials of prostate cancer was 3.71 (95% CI: 1.12, 12.26; P=0.03). Among the ICI cohorts, the common FAEs were gastrointestinal toxicity (n=12, 25%), pulmonary toxicity (n=10, 20%), cardiac toxicity (n=5, 10%), and hepatic toxicity (n=5, 10%). Conclusion: The cytotoxic T-lymphocyte-associated protein-4 (CTLA-4) inhibitors have a significantly higher risk of FAE (P=0.01), whereas programmed cell death protein 1 (PD-1) inhibitors were not. The most common CTLA-4-related FAE was gastrointestinal toxicity, and the most common PD-1-related FAE was pulmonary toxicity. Moreover, we have shown that ipilimumab has significant dose-dependent lethal toxicity.

17.
Oncol Rep ; 41(5): 2967-2974, 2019 May.
Artigo em Inglês | MEDLINE | ID: mdl-30864727

RESUMO

Estrogen receptor ß (ERß) is an important ER subtype in lung adenocarcinoma. However, the functions and mechanisms of ERß have not been fully elucidated. The aim of the present study was to investigate the biological effects and relevant mechanisms of ERß in lung adenocarcinoma. The protein expression of ERß was found to be higher in lung adenocarcinoma tissues compared with that in adjacent non­cancerous tissues (n=75, P<0.001). Of note, ERß protein expression was significantly correlated with tumor size (P=0.018), lymph node metastasis (P=0.041), clinical stage (P=0.041) and differentiation (P<0.001). In addition, ERß protein expression in A549 cells was found to be higher compared with that in human bronchial epithelial cells (HBEs). Furthermore, knockdown of ERß expression inhibited colony formation and cell invasion in vitro, whereas the number of metastatic tumors in the lungs of mice was decreased in vivo. Western blot analysis demonstrated that the expression of phosphorylated extracellular signal­regulated kinase (pERK), matrix metalloproteinase (MMP)­2 and MMP­9 was decreased by downregulation of ERß. Therefore, ERß may play an important role in lung adenocarcinoma progression via the MEK/ERK signaling axis, and it may represent a novel therapeutic target for lung adenocarcinoma in the future.


Assuntos
Adenocarcinoma de Pulmão/patologia , Receptor beta de Estrogênio/metabolismo , Neoplasias Pulmonares/patologia , Animais , Linhagem Celular Tumoral , Regulação para Baixo , Receptor beta de Estrogênio/genética , Feminino , Técnicas de Silenciamento de Genes , Humanos , Pulmão/patologia , Metástase Linfática/patologia , Sistema de Sinalização das MAP Quinases , Masculino , Camundongos , Pessoa de Meia-Idade , RNA Interferente Pequeno/metabolismo , Ensaios Antitumorais Modelo de Xenoenxerto
18.
Medicine (Baltimore) ; 98(3): e14084, 2019 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-30653124

RESUMO

BACKGROUND: Bone metastases (BM) are prevalent among lung cancer (LC) patients. Although some studies revealed associated factors for BM, each of these papers focused on a few factors. Few studies have identified the potential risk factors through a systematic review. METHODS: We searched through PubMed, MEDLINE, Web of Science, EMBASE, Cochrane Library and Cochrane Central Registerof Controlled Trials for literature from January 1990 to November 2017. The types of literature included case-control studies, cohort studies, randomized controlled trials and systematic reviews. RESULTS: From included 12 studies, we identified that lower blood calcium, T4 stage, N3 stage, P-stage III, nonsquamous, bone sialoprotein expression, elevated carcino-embryonic antigen levels were risk factors for bone metastasis in lung cancer patients. CONCLUSION: We identified that T4 stage, N3 stage, and positive bone sialoprotein expression associated with an increased risk of bone metastasis. Further studies are needed to assess these relationships and to establish the risk prediction model of bone metastasis.


Assuntos
Neoplasias Ósseas/secundário , Neoplasias Pulmonares/patologia , Cálcio/sangue , Antígeno Carcinoembrionário/metabolismo , Feminino , Humanos , Neoplasias Pulmonares/sangue , Masculino , Pessoa de Meia-Idade , Metástase Neoplásica , Estadiamento de Neoplasias , Fatores de Risco , Sialoglicoproteínas/metabolismo
19.
Hum Pathol ; 86: 163-169, 2019 04.
Artigo em Inglês | MEDLINE | ID: mdl-30633927

RESUMO

Ovarian cancer (OC) is the main cause of gynecological cancer-associated mortality. Improving the diagnosis is important for guiding clinical treatment. The present study aimed to investigate the relationship between expression of GATA6, a stem cell factor, and its prognosis in OC. In total, 521 OC cases were included. Immunohistochemistry analysis demonstrated that GATA6 was expressed in both high-grade serous carcinoma as well as non-serous tumors. High grade serous carcinoma showed a higher percentage of GATA6 positive staining. Positive staining of GATA6 showed worse overall survival (OS) in all ovarian cancers or serous and non-serous carcinoma individually. GATA6 was revealed as an independent risk factor for prognosis by multivariate Cox analysis. In all, GATA6 may present as a novel marker for poor prognosis in OC.


Assuntos
Adenocarcinoma Mucinoso/metabolismo , Carcinoma Endometrioide/metabolismo , Cistadenocarcinoma Seroso/metabolismo , Fator de Transcrição GATA6/metabolismo , Neoplasias Ovarianas/metabolismo , Adenocarcinoma Mucinoso/mortalidade , Adenocarcinoma Mucinoso/patologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Biomarcadores Tumorais , Carcinoma Endometrioide/mortalidade , Carcinoma Endometrioide/patologia , Cistadenocarcinoma Seroso/mortalidade , Cistadenocarcinoma Seroso/patologia , Feminino , Humanos , Pessoa de Meia-Idade , Neoplasias Ovarianas/mortalidade , Neoplasias Ovarianas/patologia , Prognóstico , Taxa de Sobrevida , Adulto Jovem
20.
Theor Appl Genet ; 131(12): 2529-2541, 2018 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-30244393

RESUMO

KEY MESSAGE: A SLAF-BSA approach was used to locate the RPF1 locus. The three most likely candidate genes were identified which provide a basic for cloning the resistance gene at the RPF1 locus. Spinach downy mildew is a globally devastating oomycete disease. The use of downy mildew resistance genes constitutes the most effective approach for disease management. Hence, the objective of the present study was to fine map the first-reported resistance locus RPF1. The resistance allele at this resistance locus was effective against races 1-7, 9, 11, 13, and 15 of Peronospora farinosa f. sp. spinaciae (P. effusa). The approach fine mapped RPF1 using specific-locus amplified fragment sequencing (SLAF-Seq) technology combined with bulked segregant analysis. A 1.72 Mb region localized on chromosome 3 was found to contain RPF1 based on association analysis. After screening recombinants with the SLAF markers within the region, the region was narrowed down to 0.89 Mb. Within this region, 14 R genes were identified based on the annotation information. To identify the genes involved in resistance, resequencing of two resistant inbred lines (12S2 and 12S3) and three susceptible inbred lines (12S1, 12S4, and 10S2) was performed. The three most likely candidate genes were identified via amino acid sequence analysis and conserved domain analysis between resistant and susceptible inbred lines. These included Spo12729, encoding a receptor-like protein, and Spo12784 and Spo12903, encoding a nucleotide-binding site and leucine-rich repeat domains. Additionally, based on the sequence variation in the three genes between the resistant and susceptible lines, molecular markers were developed for marker-assisted selection. The results could be valuable in cloning the RPF1 alleles and improving our understanding of the interaction between the host and pathogen.


Assuntos
Resistência à Doença/genética , Genes de Plantas , Peronospora/patogenicidade , Doenças das Plantas/genética , Spinacia oleracea/genética , Mapeamento Cromossômico , Fenótipo , Doenças das Plantas/microbiologia , Spinacia oleracea/microbiologia
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