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1.
Artigo em Inglês | MEDLINE | ID: mdl-31667572

RESUMO

PURPOSE: Trastuzumab plus chemotherapy is an effective therapy in HER2 positive advanced gastric cancer (AGC). However, the optimal maintenance treatment in patients benefited from the first line therapy remains unclear. METHODS: In this prospective observational study, patients with HER2 positive AGC who received six cycles of trastuzumab-based first line chemotherapy were divided into two arms according to the maintenance strategy: trastuzumab monotherapy (arm A) and trastuzumab plus mono-chemo-agent derived from the initial chemotherapy (arm B). The primary end point was overall survival (OS), the secondary end points were first line progression free survival (PFS), maintenance PFS, cost-effectiveness ratios (CERs), incremental cost-effectiveness ratios (ICERs) and safety. RESULTS: 30 patients were in arm A received trastuzumab monotherapy and 48 were in arm B. The clinical and pathological characteristics of two arms were well balanced. There was no significant difference of median OS (16.5 vs 20.0 months, HR 0.71 P = 0.169) or PFS (7.9 vs 11.0, HR 1.06, P = 0.892) between two arms, however, adding chemo-agent could lead to a 29% reduction in mortality risk. Adverse effects including cardiac safety were also similar. Subgroup analysis showed chemotherapy additional to trastuzumab benefited on OS in patients who had stable disease (SD) of response (HR: 0.084, P = 0.004), elder than 65 years old (HR: 0.4, P = 0.015), without liver metastasis (HR: 0.271, P = 0.008) or less than two organs of distance metastasis (HR: 0.263, P = 0.005). The average cost per patients in arm A was 153,137 RMB and 165,195 RMB in arm B. While, ICER in arm A was 1.29 times higher than arm B (CERs of two arms were 19,384 vs 15,018 RMB). CONCLUSION: Mono-chemo-agent combined with trastuzumab showed an advantage of absolute value and hazard ratio on OS, in addition to ICER of PFS for patients who benefit from the initial six cycles of trastuzumab-based first line therapy, especially in patients with certain clinical or treatment-related characterisitics. A large sample randomized trial is warranted.

2.
J Natl Cancer Inst ; 2019 Aug 10.
Artigo em Inglês | MEDLINE | ID: mdl-31400201

RESUMO

BACKGROUND: Isocitrate dehydrogenase (IDH)-wild-type (WT) glioblastoma (GBM) accounts for 90% of all GBMs, while only 27% of IDH-WT-GBMs have p53 mutations. However, the tumor surveillance function of WT-p53 in GBM is subverted by mechanisms that are not fully understood. METHODS: We investigated the proteolytic inactivation of WT-p53 by asparaginyl endopeptidase (AEP) and its effects on GBM progression in cancer cells, murine models, and patients' specimens using biochemical and functional assays. The sera of healthy donors (n = 48) and GBM patients (n = 20) were examined by enzyme-linked immunosorbent assay. Furthermore, effects of AEP inhibitors on GBM progression were evaluated in murine models (n = 6-8 per group). The statistical significance between groups was determined using two-tailed Student t tests. RESULTS: We demonstrate that AEP binds to and directly cleaves WT-p53, resulting in the inhibition of WT-p53-mediated tumor suppressor function in both tumor cells and stromal cells via extracellular vesicle communication. High expression of uncleavable p53-N311A-mutant rescue AEP-induced tumorigenesis, proliferation, and anti-apoptotic abilities. Knockdown or pharmacological inhibition of AEP reduced tumorigenesis and prolonged survival in murine models. However, overexpression of AEP promoted tumorigenesis and shortened the survival time. Moreover, high AEP levels in GBM tissues were associated with a poor prognosis of GBM patients (n = 83; HR = 3.94 (95%CI=1.87-8.28), p<.001). A correlation was found between high plasma AEP levels and a larger tumor size in GBM patients (r = 0.6, p=.03), which decreased dramatically after surgery. CONCLUSION: Our results indicate that AEP promotes GBM progression via inactivation of WT-p53 and may serve as a prognostic and therapeutic target for GBM.

3.
Clin Chem Lab Med ; 57(10): 1501-1510, 2019 Sep 25.
Artigo em Inglês | MEDLINE | ID: mdl-31339850

RESUMO

Background Evaluating the tumor RAS/BRAF status is important for treatment selection and prognosis assessment in metastatic colorectal cancer (mCRC) patients. Correction of artifacts from library preparation and sequencing is essential for accurately analyzing circulating tumor DNA (ctDNA) mutations. Here, we assessed the analytical and clinical performance of a novel amplicon-based next-generation sequencing (NGS) assay, Firefly™, which employs a concatemer-based error correction strategy. Methods Firefly assay targeting KRAS/NRAS/BRAF/PIK3CA was evaluated using cell-free DNA (cfDNA) reference standards and cfDNA samples from 184 mCRC patients. Plasma results were compared to the mutation status determined by ARMS-based PCR from matched tissue. Samples with a mutation abundance below the limit of detection (LOD) were retested again by droplet digital polymerase chain reaction (ddPCR) or NGS. Results The Firefly assay demonstrated superior sensitivity and specificity with a 98.89% detection rate at an allele frequency (AF) of 0.2% for 20 ng cfDNA. Generally, 40.76% and 48.37% of the patients were reported to be positive by NGS of plasma cfDNA and ARMS of FFPE tissue, respectively. The concordance rate between the two platforms was 80.11%. In the pre-treatment cohort, the concordance rate between plasma and tissue was 93.33%, based on the 17 common exons that Firefly™ and ARMS genotyped, and the positive percent agreement (PPA) and negative percent agreement (NPA) for KRAS/NRAS/BRAF/PIK3CA were 100% and 99.60%, respectively. Conclusions Total plasma cfDNA detected by Firefly offers a viable complement for mutation profiling in CRC patients, given the high agreement with matched tumor samples. Together, these data demonstrate that Firefly could be routinely applied for clinical applications in mCRC patients.

4.
Environ Health Perspect ; 127(6): 67003, 2019 06.
Artigo em Inglês | MEDLINE | ID: mdl-31166131

RESUMO

BACKGROUND: The pyrethroid deltamethrin (DM) is broadly used for insect control. Although DM hyperexcites neuronal networks by delaying inactivation of axonal voltage-dependent [Formula: see text] channels, this mechanism is unlikely to mediate neurotoxicity at lower exposure levels during critical perinatal periods in mammals. OBJECTIVES: We aimed to identify mechanisms by which acute and subchronic DM altered axonal and dendritic growth, patterns of synchronous [Formula: see text] oscillations (SCOs), and electrical spike activity (ESA) functions critical to neuronal network formation. METHODS: Measurements of SCOs using [Formula: see text] imaging, ESA using microelectrode array (MEA) technology, and dendritic complexity using Sholl analysis were performed in primary murine cortical neurons from wild-type (WT) and/or ryanodine receptor 1 ([Formula: see text]) mice between 5 and 14 d in vitro (DIV). [Formula: see text] binding analysis and a single-channel voltage clamp were utilized to measure engagement of RyRs as a direct target of DM. RESULTS: Neuronal networks responded to DM ([Formula: see text]) as early as 5 DIV, reducing SCO amplitude and depressing ESA and burst frequencies by 60-70%. DM ([Formula: see text]) enhanced axonal growth in a nonmonotonic manner. [Formula: see text] enhanced dendritic complexity. DM stabilized channel open states of RyR1, RyR2, and cortical preparations expressing all three isoforms. DM ([Formula: see text]) altered gating kinetics of RyR1 channels, increasing mean open time, decreasing mean closed time, and thereby enhancing overall open probability. SCO patterns from cortical networks expressing [Formula: see text] were more responsive to DM than WT. [Formula: see text] neurons showed inherently longer axonal lengths than WT neurons and maintained less length-promoting responses to nanomolar DM. CONCLUSIONS: Our findings suggested that RyRs were sensitive molecular targets of DM with functional consequences likely relevant for mediating abnormal neuronal network connectivity in vitro. https://doi.org/10.1289/EHP4583.

5.
Oncologist ; 24(10): 1311-e989, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31239311

RESUMO

LESSONS LEARNED: The NEO-CLASSIC study provided valuable insight for the clinical efficacy and tolerability profiles of perioperative chemotherapy with oxaliplatin and capecitabine, plus gastrectomy, in patients with localized resectable gastric cancer.The study was designed to explore the potential survival benefits of an eight-cycle, perioperative oxaliplatin and capecitabine (XELOX) schedule in the above-mentioned setting and to explore the feasibility of prolonging the cycles of preoperative chemotherapy. The projected endpoint was not met. BACKGROUND: This multicenter, open-label study (NEO-CLASSIC) evaluated the efficacy and safety of oxaliplatin and capecitabine (XELOX), plus D2 gastrectomy, in localized resectable gastric cancer. METHODS: Patients aged 18-75 years with histologically-confirmed gastric adenocarcinoma (stage T2-4a/N+M0) were given eight cycles of XELOX (four preoperatively, four postoperatively). Each 3-week cycle comprised capecitabine 1,000 mg/m2 twice daily on days 1-14 and oxaliplatin 130 mg/m2 on day 1. Curative D2 gastrectomy was scheduled 2-4 weeks after the last preoperative cycle. The primary objective of the study was to determine the objective response rate (ORR) of XELOX in the preoperative setting. Sample size was calculated by assuming that a minimum of 47 cases would be required to increase the ORR by 15% (from 40% to 55%). With an estimated 10% dropout rate, 55 patients would have to be recruited. RESULTS: Fifty-five patients were enrolled, and one was excluded because of screening failure. R0 resections were achieved in 45 of 54 intent-to-treat patients (83.3%), and four patients received R1 resections (Fig. 1). There were no complete responses, 27 (50.0%) partial responses, 22 cases (40.7%) of stable disease, and 4 (7.4%) of progressive disease. The objective response rate was 50.0%. Median follow-up was 52.97 months; 30 patients (55.6%) had disease progression (Table 1), and median progression-free survival was 20.10 (95% confidence interval: 4.31-35.89) months; median overall survival was 30.77 months (95% confidence interval was not yet available) (Fig. 2). Fifty-four patients completed 209 cycles of preoperative chemotherapy; 42 patients received 133 cycles of postoperative chemotherapy (Table 3). The rate of grade 3-4 adverse events was 8.5% (29/342 cycles); the most frequent events were neutropenia (9/342 cycles) and leukopenia (4/342 cycles). CONCLUSION: These findings suggest that combination therapy with capecitabine and oxaliplatin as perioperative chemotherapy, followed by D2 gastrectomy, is effective and safe in late-stage, locally advanced gastric cancer. Although enrollment exceeded the 47 patients required to identify an increase in the ORR by 15% (from 40% to 55%), results did not meet the primary endpoint.

6.
Fitoterapia ; 137: 104150, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-30995564

RESUMO

Schefflera kwangsiensis Merr. ex H.L. Li (Araliaceae) is a widely used traditional Chinese medicine for pain management in the clinic. In the present study, we isolated a previously undescribed lupane saponin, designated as schekwanglupaside C (Sch C) from the ethanolic extract of S. kwangsiensis. The structure of Sch C was determined by comprehensive spectroscopic and spectrometric analyses and chemical degradation. In primary cultured cortical neurons, Sch C altered the pattern of spontaneous Ca2+ oscillation (SCO) with a slight increase in the frequency of SCO right after addition and a gradual decrease in the frequency and amplitude of SCO, that dynamic change mimicked by an activator of sarcoplasmic reticulum Ca2+-ATPase (SERCA). The IC50 values for Sch C suppression of the frequency and amplitude of SCO were 1.75 and 2.51 µM, respectively. Furthermore, we demonstrated that Sch C is a potent SERCA activator (EC50 = 1.20 µM). Given the pivotal role of SERCA in the progression of neuropathic pain and neurodegenerative diseases, Sch C represents a new drug lead compound to develop the treatment of neuropathic pain and Alzheimer's disease.


Assuntos
Araliaceae/química , Neurônios/efeitos dos fármacos , Saponinas/farmacologia , ATPases Transportadoras de Cálcio do Retículo Sarcoplasmático/metabolismo , Triterpenos/farmacologia , Animais , Cálcio/metabolismo , Células Cultivadas , China , Feminino , Masculino , Camundongos Endogâmicos C57BL , Estrutura Molecular , Compostos Fitoquímicos/isolamento & purificação , Compostos Fitoquímicos/farmacologia , Componentes Aéreos da Planta/química , Saponinas/isolamento & purificação , Retículo Sarcoplasmático/enzimologia , Triterpenos/isolamento & purificação
7.
Sci Rep ; 9(1): 3324, 2019 Mar 01.
Artigo em Inglês | MEDLINE | ID: mdl-30824811

RESUMO

Streptococcus pneumoniae (pneumococcus) is the most common respiratory pathogen worldwide. Nasopharyngeal carriage with S. pneumoniae is the major source of lower respiratory tract infection and horizontal spread among children. Investigating nasopharyngeal S. pneumoniae is crucial for clinicians to control pneumococcus disease. Here, we retrospectively analyzed clinical information of 5,960 hospitalized children, focusing on pneumonia children less than five years with positive nasopharyngeal pneumococcal cultures. Nasopharyngeal aspirates (NPAs) were collected between June 2009 and December 2016, which were outside the pneumococcal conjugate vaccine(PCV) period. NPAs were subjected to common bacterial culture and antibiotic susceptibility tests, and serotypes were identified by both multiplex PCR and DNA sequencing. Results clearly revealed that clinical manifestations of the children whose NPAs were S. pneumoniae culture positive were serious, especially in those less than twelve months old. Fifteen different serotypes of nasopharyngeal S. pneumoniae were detected, the most common ones being 19F (35.2%), 6A/B (23.8%), 19A (11.4%), 15B/C (9.3%) and 23F (7.8%). Eight serotypes, accounting for 85.5% of the isolates, corresponded to the PCV13 serotypes. Approximately one-third of all S. pneumoniae strains were susceptible to penicillin. Overall, we consider nasopharyngeal S. pneumoniae culture is beneficial in assessing the situations of pneumonia children. Moreover, PCV13 could be useful in preventing pneumococcal disease in Chongqing, China.

8.
Gastric Cancer ; 2018 Nov 13.
Artigo em Inglês | MEDLINE | ID: mdl-30426294

RESUMO

BACKGROUND: To compare the efficacy of oxaliplatin-based and oxaliplatin-free adjuvant chemotherapies in patients with different Lauren type gastric cancers after D2 gastrectomy. METHODS: From our established gastric cancer database, patients with pathological stage II and III gastric cancer who received adjuvant chemotherapy after D2 gastrectomy at Zhongshan Hospital of Fudan University were analyzed. Patients who received different adjuvant chemotherapy regimens were divided into two subgroups: oxaliplatin-based and oxaliplatin-free subgroup. Clinical outcomes were analyzed according to pathological stage and different Lauren types. RESULTS: From Jan 2010 to June 2017, a total of 580 patients met all the eligibility criteria and were enrolled. The median DFS for all the patients was 24.37 months and the median OS was 56.70 months. In patients with intestinal type gastric cancer, the median DFS of the oxaliplatin-based subgroup was significantly longer than that of oxaliplatin-free subgroup (48.73 vs. 18.33 months, P < 0.001). The median OS was not reached in the oxaliplatin-based subgroup and 54.33 months in the oxaliplatin-free subgroup (P = 0.006). In patients with diffuse type gastric cancer, neither DFS nor OS differed significantly between two subgroups. In multivariate analysis, oxaliplatin-based adjuvant chemotherapy was independent positive predictor of DFS (HR 0.40; 95% CI 0.28-0.59; P < 0.001) and OS (HR 0.35; 95% CI 0.20-0.62; P < 0.001) in patients with intestinal type gastric cancer. CONCLUSIONS: The results of our study suggested that oxaliplatin-based adjuvant chemotherapy was more effective in patients with intestinal type gastric cancer after D2 gastrectomy but showed no more survival benefit in patients with diffuse type.

9.
Cell Physiol Biochem ; 50(2): 768-782, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30308491

RESUMO

BACKGROUND/AIMS: Non-radical primary tumour resection (PTR) of asymptomatic metastatic colorectal cancer (mCRC) can prolong survival time of some patients. Patients with mutated RAS gene have worse survival outcome. This study aimed to investigate the impact of RAS gene mutations on the prognosis of asymptomatic unresectable mCRC patients who underwent PTR. METHODS: A retrospective observational cohort study was deduced among mCRC patients who experienced PTR or had intact primary tumour (IPT). All of them had the primary tumour tissue genotyping tested for RAS (KRAS and NRAS) gene mutations. The tumour-related overall survival (OS) time and progression-free survival (PFS) time was estimated. From January 2011 to June 2014, 421 mCRC patients with asymptomatic, unresectable, metastatic disease were enrolled in this study. Among them, 282 patients underwent PTR and 139 patients had IPT. RESULTS: The mutation rate of RAS was 53.8% (221/411). With a median followed-up time of 46.5 months, the overall survival time of mCRC patients harboring wtRAS or mtRAS was 28.0 versus 22.0 months (p = 0.043) in PTR group and was 21.6 versus 17.8 months (p=0.071) in IPT groups. A Multivariate regression analysis suggested that RAS gene (p=0.039, HR=1.288,95%CI [1.072∼2.911]), metastatic organ number (p=0.033, HR=3.091,95%CI [1.090∼5.755]) and systemic therapy response (p=0.019, HR=0.622,95%CI [0.525∼0.811]) were independent prognostic factors in PTR population. CONCLUSION: We found that wild-type RAS gene was a favorable factor for the asymptomatic unresectable mCRC patients experiencing PTR.


Assuntos
Neoplasias Colorretais/patologia , Proteínas ras/genética , Adulto , Idoso , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Neoplasias Colorretais/tratamento farmacológico , Neoplasias Colorretais/mortalidade , Intervalo Livre de Doença , Feminino , Genótipo , Humanos , Estimativa de Kaplan-Meier , Masculino , Pessoa de Meia-Idade , Mutação , Metástase Neoplásica , Prognóstico , Modelos de Riscos Proporcionais , Análise de Regressão , Estudos Retrospectivos
10.
Biomed Res Int ; 2018: 5920608, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-29662888

RESUMO

Colorectal cancer (CRC) is the fifth leading cause of cancer death and the fifth most commonly diagnosed cancer in China. Approximately, 25% of CRC was in the advanced stage as diagnosed, and 40% of patients with CRC progress to metastatic colorectal cancer (mCRC). RAS mutation status is now routinely used to select their therapy. But it is still a question whether RAS mutation status is a prognostic marker. In our study, we detected RAS mutation, immunoscore (IS), and PD-L1 expression in 60 Chinese mCRC patients who received palliative operation. The Kaplan-Meier survival analysis showed that the overall survival (OS) in patients with RAS wild type was better than those with RAS mutated type. Moreover, in multivariate analysis, RAS mutation and PD-L1 expression were demonstrated to be the independent negative prognostic factors for OS (P = 0.044, HR: 0.258, and 95% CI: 0.069-0.967; P = 0.048, HR: 0.276, and 95% CI: 0.077-0,988). All results suggested that, combined with IS, PD-L1 expression and RAS status may be the prognostic indicators for mCRC patients with palliative operation.


Assuntos
Antígeno B7-H1/metabolismo , Neoplasias Colorretais/patologia , Neoplasias Colorretais/cirurgia , Cuidados Paliativos , Proteínas ras/genética , Neoplasias Colorretais/genética , Feminino , Regulação Neoplásica da Expressão Gênica , Humanos , Masculino , Pessoa de Meia-Idade , Análise Multivariada , Metástase Neoplásica , Prognóstico , Análise de Sobrevida
11.
Oncol Rep ; 39(5): 2235-2242, 2018 May.
Artigo em Inglês | MEDLINE | ID: mdl-29565456

RESUMO

FoxO transcription factors are important regulators of cell survival in response to a variety of stress stimuli and play vital functions in tumor progression. However, the functions and underlying regulators of FoxO3a in colorectal cancer (CRC) have not been fully elucidated. The aim of the current study was to identify the functions of FoxO3a in CRC and characterize the transcription elements within the promoter region of FoxO3a. The expression of FoxO3a was upregulated in response to hypoxic and oxidative stress stimuli. Furthermore, knockdown of FoxO3a significantly reduced cell proliferation and migration ability, while it promoted the response to cetuximab treatment. In addition, it was revealed that knockdown of FoxO3a reduced tumor progression in vivo. A mechanistic study found that plenty of putative SP1 sites were identified in the FoxO3a promoter. Luciferase reporter assay revealed that a region corresponding to the SP1 binding sites located between ­2,000 and ­1,037 bp of FoxO3a promoter was essential for the transcriptional activity. Co-transfection of a SP1 expression vector with the reporter constructs markedly increased luciferase activity. Collectively, these results indicated that SP1­dependent promoter elements drive FoxO3a gene transcription in colorectal CRC, and indicated that SP1 upregulated FoxO3a is critical for CRC progression.


Assuntos
Neoplasias Colorretais/patologia , Proteína Forkhead Box O3/genética , Proteína Forkhead Box O3/metabolismo , Fator de Transcrição Sp1/metabolismo , Regulação para Cima , Animais , Sítios de Ligação , Células CACO-2 , Movimento Celular , Proliferação de Células , Neoplasias Colorretais/genética , Neoplasias Colorretais/metabolismo , Progressão da Doença , Proteína Forkhead Box O3/química , Regulação Neoplásica da Expressão Gênica , Células HT29 , Humanos , Camundongos , Transplante de Neoplasias , Regiões Promotoras Genéticas , Transcrição Genética
12.
Sci Rep ; 8(1): 1379, 2018 01 22.
Artigo em Inglês | MEDLINE | ID: mdl-29358739

RESUMO

Mice use vision to navigate and avoid predators in natural environments. However, their visual systems are compact compared to other mammals, and it is unclear how well mice can discriminate ethologically relevant scenes. Here, we examined natural scene discrimination in mice using an automated touch-screen system. We estimated the discrimination difficulty using the computational metric structural similarity (SSIM), and constructed psychometric curves. However, the performance of each mouse was better predicted by the mean performance of other mice than SSIM. This high inter-mouse agreement indicates that mice use common and robust strategies to discriminate natural scenes. We tested several other image metrics to find an alternative to SSIM for predicting discrimination performance. We found that a simple, primary visual cortex (V1)-inspired model predicted mouse performance with fidelity approaching the inter-mouse agreement. The model involved convolving the images with Gabor filters, and its performance varied with the orientation of the Gabor filter. This orientation dependence was driven by the stimuli, rather than an innate biological feature. Together, these results indicate that mice are adept at discriminating natural scenes, and their performance is well predicted by simple models of V1 processing.

13.
Biomed Pharmacother ; 97: 1138-1146, 2018 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-29136952

RESUMO

BACKGROUND: Cetuximab is one of the most widely used epidermal growth factor receptor (EGFR) inhibitors to treat patients with metastatic colorectal cancer (mCRC) harboring wild-type of RAS/RAF status. However, primary and acquired resistance to cetuximab is often found during target therapy. METHODS: To gain insights into the functions of long non-coding RNA (lncRNA) in cetuximab resistance, we used a lncRNA-mining approach to distinguish lncRNA specific probes in Affymetrix HG-U133A 2.0 arrays. Then we performed lncRNA expression profiling in a cetuximab treated mCRC cohort from Gene Expression Ominus (GEO). The potential lncRNAs were further validated in acquired cetuximab resistant cell lines and clinical samples of our hospital. The functions and associated pathways of the prognostic lncRNA were predicted by GO and KEGG analyses. RESULTS: 249 lncRNA-specific probe sets (corresponding to 212 lncRNAs) were represented in Affymetrix HG-U133A 2.0 arrays. We found that 9 lncRNAs were differentially expressed between disease control group (DCG) and non-responders, and 5 of these 9 lncRNAs were significantly related with the progression-free survival (PFS) of the patients. Among those 5 lncRNAs, POU5F1P4 was also down-regulated in acquired cetuximab resistant cells, as well as in cetuximab resistant patients. Downregulation of POU5F1P4 decreased the sensitivity of colorectal cancer cells to cetuximab. CONCLUSION: Our findings indicate the potential roles of lncRNAs in cetuximab resistance, and may provide the useful information for discovery of new biomarkers and therapeutic targets.


Assuntos
Antineoplásicos Imunológicos/farmacologia , Cetuximab/farmacologia , Neoplasias Colorretais/tratamento farmacológico , RNA Longo não Codificante/genética , Biomarcadores Tumorais/metabolismo , Células CACO-2 , Neoplasias Colorretais/genética , Neoplasias Colorretais/patologia , Intervalo Livre de Doença , Resistencia a Medicamentos Antineoplásicos , Receptores ErbB/antagonistas & inibidores , Regulação Neoplásica da Expressão Gênica , Humanos , Metástase Neoplásica , Inibidores de Proteínas Quinases/farmacologia , Quinases raf/genética , Proteínas ras/genética
14.
Oncotarget ; 7(49): 80888-80900, 2016 Dec 06.
Artigo em Inglês | MEDLINE | ID: mdl-27825133

RESUMO

Resistance to epidermal growth factor receptor (EGFR) targeted monoclonal antibody therapy represents a clinical challenge in patients suffered from RAS wild-type (WT) metastatic colorectal cancer (mCRC). However, the molecular mechanisms and key factors conferring this resistance are largely unknown. Forkhead transcription factors of the O class 3a (FoxO3a), an important regulator of cell survival, has been reported with dual functions in tumor recently. In this study, we found that FoxO3a was highly expressed in cetuximab resistant CRC tissues compared with cetuximab sensitive tissues. We therefore further analyzed its function in induced cetuximab resistant RAS-WT CRC cells (Caco2-CR) and intrinsic resistant cells with BRAF mutation (HT29). We found that FoxO3a was significantly up-regulated in Caco2-CR as well as in cetuximab treated HT29 cells. Knockdown of FoxO3a could sensitize these cells to cetuximab treatment with reduced cell proliferation and migration ability. Further, biochemical experiments demonstrated that FoxO3a directly bind to c-Myc promoter and activated the transcription of the c-Myc gene, thus participated in regulating of c-Myc downstream genes, including ACO2, LARS2, MRPL12 and PKM2 in these resistant cells. Moreover, knockdown of c-Myc elevated cell apoptosis to cetuximab treatment and suppressed cell proliferation and migration ability consistently. Altogether, our study indicates that FoxO3a might be a key regulator in cetuximab resistance through up-regulating c-Myc in colorectal cancer targeted therapy.


Assuntos
Antineoplásicos Imunológicos/farmacologia , Movimento Celular , Cetuximab/farmacologia , Neoplasias Colorretais/tratamento farmacológico , Resistencia a Medicamentos Antineoplásicos , Proteína Forkhead Box O3/metabolismo , Genes ras , Proteínas Proto-Oncogênicas c-myc/metabolismo , Animais , Apoptose/efeitos dos fármacos , Sítios de Ligação , Células CACO-2 , Proliferação de Células/efeitos dos fármacos , Neoplasias Colorretais/genética , Neoplasias Colorretais/metabolismo , Neoplasias Colorretais/patologia , Resistencia a Medicamentos Antineoplásicos/genética , Proteína Forkhead Box O3/genética , Regulação Neoplásica da Expressão Gênica , Células HT29 , Humanos , Camundongos Nus , Mutação , Invasividade Neoplásica , Regiões Promotoras Genéticas , Proteínas Proto-Oncogênicas B-raf/genética , Proteínas Proto-Oncogênicas c-myc/genética , Interferência de RNA , Transdução de Sinais , Fatores de Tempo , Transcrição Genética , Transfecção , Carga Tumoral/efeitos dos fármacos
15.
Cell Physiol Biochem ; 39(3): 1239-46, 2016.
Artigo em Inglês | MEDLINE | ID: mdl-27595400

RESUMO

BACKGROUND: The effect of primary tumour resection (PTR) among metastatic colorectal cancer (mCRC) patients remains controversial. Combination chemotherapy with bevacizumab could improve the clinical outcomes of these patients, which might change the importance of PTR in the multi-disciplinary treatment pattern. METHODS: We performed a non-randomized prospective controlled study of mCRC pts whose performance status (PS) scored ≤2 and who received bevacizumab combination chemotherapy (FOLFOX/XELOX/FOLFIRI) as a first-line therapy. These patients were classified into the PTR group and the IPT (intact primary tumour) group according to whether they underwent PTR before receiving the systemic therapy. The progression free survival (PFS) time and overall survival (OS) time, which were recorded from the start of the primary diagnosis until disease progression and death or last follow-up, were analysed. We also compared severe clinical events (such as emergency surgery, radiation therapy, and stent plantation) between the two groups. RESULTS: One hundred and nighty-one mCRC pts (108 male patients and 93 female patients) were entered in this prospective observational study. The median age was 57.5 years old. The clinical characteristics (age, gender, performance status, primary tumour site, RAS status, and the number of metastatic organs) did not significantly differ between the two groups. The median PFS and OS times of the PTR group were superior than those of the IPT group (10.0 vs 7.8 months, p < 0.01 and 22.5 vs 17.8 months, p < 0.01, respectively). The incidences of adverse events associated with systemic therapy were similar between the two groups. Specifically, sixteen patients (21.9%, 16/73) with IPT developed significant primary tumour-related complications, such as bleeding, obstruction or even perforation. Among these patients, five underwent emergency surgery, three patients received a stent, and eight patients underwent radiation therapy. CONCLUSIONS: The mCRC patients who received PTR and bevacizumab combination chemotherapy had better clinical outcomes than patients who did not receive PTR. PTR also decreased the incidence of severe clinical events and improved quality of life.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Bevacizumab/uso terapêutico , Camptotecina/análogos & derivados , Neoplasias Colorretais/cirurgia , Neoplasias Colorretais/terapia , Desoxicitidina/análogos & derivados , Fluoruracila/análogos & derivados , Adulto , Idoso , Camptotecina/uso terapêutico , Estudos de Casos e Controles , Neoplasias Colorretais/mortalidade , Neoplasias Colorretais/patologia , Desoxicitidina/uso terapêutico , Progressão da Doença , Feminino , Fluoruracila/uso terapêutico , Raios gama/uso terapêutico , Humanos , Leucovorina/uso terapêutico , Metástase Linfática , Masculino , Pessoa de Meia-Idade , Compostos Organoplatínicos/uso terapêutico , Estudos Prospectivos , Qualidade de Vida , Stents , Análise de Sobrevida
16.
Oncotarget ; 7(46): 76298-76307, 2016 11 15.
Artigo em Inglês | MEDLINE | ID: mdl-27602586

RESUMO

Purpose We assessed the effectiveness of EOX (capecitabine, oxaliplatin and epirubicin) compared with XELOX (capecitabine and oxaliplatin) as preoperative chemotherapy for initially unresectable locally advanced gastric cancer.Methods This is a prospective observational study. Patients with unresectable locally advanced gastric cancer were performed EOX regimen or XELOX regimen at the discretion of the investigators. They were assessed for response every 2 cycles by CT (computed tomography) scan. A multidisciplinary team reassessed resectability after 4 cycles. The primary endpoint was the response rate. Secondary end points included the R0 resection rate, survival and adverse events.Results From November 2008 to May 2015, 242 patients were enrolled; 112 of them were assigned to EOX regimen and 130 to XELOX regimen. The response rates were 33.0% and 33.8% respectively in EOX group and XELOX group (P = 0.997). After 4 cycles of chemotherapy, 63 patients (56.3%) in EOX group and 81 patients (62.3%) in XELOX group received radical operation (P = 0.408). There was no significant difference in progress-free survival (PFS, 12.0m vs. 15.4m, P = 0.925) and overall survival (OS, 25.7m vs. 29.0m, P = 0.783) in two groups. In addition, more adverse effects occurred in EOX group, such as more leucopenia (22.3% vs. 10.0%, P = 0.014), neutropenia (23.2% vs. 11.5%, P = 0.025), fatigue (11.6% vs. 3.8%, P = 0.041) and vomiting (10.7% vs. 2.3%, P = 0.015).Conclusions For unresectable locally advanced gastric cancer patients, XELOX regimen showed similar effects in response rate, radical resection rate and survival benefits, but with less toxicity effects.


Assuntos
Adenocarcinoma/tratamento farmacológico , Adenocarcinoma/patologia , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Desoxicitidina/análogos & derivados , Fluoruracila/análogos & derivados , Neoplasias Gástricas/tratamento farmacológico , Neoplasias Gástricas/patologia , Adenocarcinoma/mortalidade , Adenocarcinoma/cirurgia , Adolescente , Adulto , Idoso , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Capecitabina/administração & dosagem , Terapia Combinada , Desoxicitidina/efeitos adversos , Desoxicitidina/uso terapêutico , Epirubicina/administração & dosagem , Feminino , Fluoruracila/efeitos adversos , Fluoruracila/uso terapêutico , Humanos , Masculino , Pessoa de Meia-Idade , Metástase Neoplásica , Estadiamento de Neoplasias , Cuidados Pré-Operatórios , Estudos Prospectivos , Neoplasias Gástricas/mortalidade , Neoplasias Gástricas/cirurgia , Análise de Sobrevida , Resultado do Tratamento , Adulto Jovem
17.
Oncotarget ; 7(31): 50656-50665, 2016 Aug 02.
Artigo em Inglês | MEDLINE | ID: mdl-27409420

RESUMO

INTRODUCTION: Trastuzumab plus chemotherapy is the standard first-line regimen in HER2 positive advanced gastric cancer (AGC), but lack of data in post-progression treatment. So, it is worth evaluating the efficacy of continuing trastuzumab after failure of the first-line trastuzumab based treatment. METHODS: 59 patients were enrolled from Zhongshan Hospital Fudan University, Sun Yat-sen University Cancer Center and Peking University Cancer Hospital between September 2012 and Oct 2015. Patients were divided into two groups according to the second line regimens: with or without trastuzumab. The primary endpoint was progression free survival of second line therapy (PFS2). Secondary end points included overall survival (OS), response rate, and adverse events (AEs). RESULTS: Baseline factors were well balanced between two groups. 32 patients treated with trastuzumab plus second line chemotherapy (group A) and 27 patients received chemotherapy alone (group B). The median follow-up time was 7.60 months (range 1.50-32.50). Longer median PFS2 was observed in group A than in group B (3.1 vs 2.0 months, P=0.008). There was no significant differences of median OS2 calculating from the second line therapy (10.5 vs 6.5 months, P=0.172) between two groups. Response rate was 9.3% in group A compared with 3.7% in group B (P=0.617). AEs were similar in two groups including cardiac safety. Subgroup analysis showed that factors of male, age<65, good performance status, HER2 immunohistochemical (IHC) 2+ and poor response to first line indicated superior PFS2 in patients continuing trastuzumab to those treated with chemotherapy alone. CONCLUSION: Continuing treatment of trastuzumab beyond first line therapy progression showed effective and safe in AGC.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Receptor ErbB-2/metabolismo , Neoplasias Gástricas/tratamento farmacológico , Trastuzumab/administração & dosagem , Idoso , Antineoplásicos/administração & dosagem , Progressão da Doença , Intervalo Livre de Doença , Feminino , Seguimentos , Humanos , Estimativa de Kaplan-Meier , Masculino , Pessoa de Meia-Idade , Prognóstico , Estudos Prospectivos , Neoplasias Gástricas/metabolismo , Resultado do Tratamento
18.
Oncotarget ; 7(23): 34356-70, 2016 Jun 07.
Artigo em Inglês | MEDLINE | ID: mdl-27102302

RESUMO

Asparaginyl endopeptidase (AEP) is a lysosomal protease and overexpressive in gastric cancer. AEP was higher expressive in peritoneal metastatic loci than that in primary gastric cancer. Then we overexpressed AEP or knocked it down with a lentiviral vector in gastric cancer cell lines and detected the cell cycle arrest and the changes of the invasive and metastatic ability in vitro and in vivo. When AEP was knocked-down, the proliferative, invasive and metastatic capacity of gastric cancer cells were inhibited, and the population of sub-G1 cells increased. The expressive level of twist, which is a transcriptional factor, decreased significantly, and the epithelial markers' expression of EMT, E-cadherin increased, but that of the mesenchymal markers, N-cadherin, ß-catenin and Vimentin decreased, if AEP was knocked down. These results showed that AEP could promote invasion and metastasis by modulating EMT. We used phosphorylation-specific antibody microarrays to investigate the mechanism that AEP promotes gastric cancer invasion and metastasis, and found that the phosphorylation level of AKT and MAPK signaling pathways were decreased significantly if AEP was knocked-down. Therefore, AKT and MAPK signaling pathways took part in the modulation.


Assuntos
Cisteína Endopeptidases/genética , Cisteína Endopeptidases/metabolismo , Transição Epitelial-Mesenquimal/fisiologia , Neoplasias Gástricas/genética , Neoplasias Gástricas/patologia , Animais , Caderinas/metabolismo , Pontos de Checagem do Ciclo Celular , Linhagem Celular Tumoral , Proliferação de Células/genética , Regulação Neoplásica da Expressão Gênica , Humanos , Sistema de Sinalização das MAP Quinases/fisiologia , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Nus , Invasividade Neoplásica/genética , Metástase Neoplásica/genética , Metástase Neoplásica/patologia , Proteínas Nucleares/metabolismo , Fosforilação , Proteínas Proto-Oncogênicas c-akt/metabolismo , Proteína 1 Relacionada a Twist/metabolismo , Vimentina/metabolismo , beta Catenina/metabolismo
19.
Oncotarget ; 7(23): 34773-84, 2016 Jun 07.
Artigo em Inglês | MEDLINE | ID: mdl-27127880

RESUMO

Forkhead box O3A (FOXO3a) is an important transcription factor involved in various human cancers. However, the role of FOXO3a in regulating the invasion and metastasis of gastric cancer cells has not been clarified. Here, we report that FOXO3a overexpression promoted migration and invasion of gastric cancer cells by upregulating cathepsin L. FOXO3a knockdown suppressed migration and invasion and also downregulated cathepsin L expression in gastric cancer cells. Silencing cathepsin L in these cells suppressed FOXO3a overexpression-induced cell migration and invasion. Mechanistic studies revealed that FOXO3a increased cathepsin L promoter activation, and cathepsin L overexpression repressed E-cadherin expression, causing gastric cancer cells to undergo epithelial-mesenchymal transition (EMT). Our data reveal a previously unexplored function of FOXO3a in gastric cancer invasion by regulating proteins involved in extracellular matrix (ECM) degradation and EMT. We suggest that FOXO3a may be of prognostic value and a potential therapeutic target in blocking tumor metastasis.


Assuntos
Catepsina L/metabolismo , Transição Epitelial-Mesenquimal/fisiologia , Matriz Extracelular/metabolismo , Proteína Forkhead Box O3/metabolismo , Neoplasias Gástricas/patologia , Caderinas/biossíntese , Catepsina L/genética , Linhagem Celular Tumoral , Movimento Celular/genética , Transição Epitelial-Mesenquimal/genética , Proteína Forkhead Box O3/biossíntese , Proteína Forkhead Box O3/genética , Humanos , Invasividade Neoplásica/genética , Regiões Promotoras Genéticas/genética , Neoplasias Gástricas/genética
20.
Oncotarget ; 7(10): 11380-96, 2016 Mar 08.
Artigo em Inglês | MEDLINE | ID: mdl-26863631

RESUMO

This study assessed second-line continued use of cetuximab for treatment of unresectable metastatic colorectal cancer (mCRC) after disease progression during first-line cetuximab-based therapy. Consecutive patients with wild-type KRAS exon 2 and unresectable mCRC were retrospectively enrolled after disease progression during first-line cetuximab-based chemotherapy. Second-line continued cetuximab plus changed chemotherapy (cetuximab continuation group, n = 102) was compared with changed chemotherapy only (chemotherapy only group, n = 96) with respect to treatment efficacy and safety endpoints. NRAS and other KRAS genotypes were also detected as a post hoc analysis. The cetuximab continuation group showed better progression-free survival (median, 6.3 vs. 4.5 months, P = 0.004), overall survival (median, 17.3 vs. 14.0 months, P < 0.001) and disease control rate (70.6% vs. 53.1%, P = 0.011), and a potentially better overall response rate (18.6% vs. 9.4%, P = 0.062) than the chemotherapy only group. These benefits were seen mainly in patients with all RAS wild-type and exhibiting first-line early tumor shrinkage (ETS). For patients with other RAS mutations or who did not achieve first-line ETS, there was no difference between the two groups. These findings suggest that for patients with all RAS wild-type and unresectable mCRC who had disease progression during first-line cetuximab-based treatment, second-line continued cetuximab is effective. Moreover, ETS during first-line cetuximab-based treatment may be predictive of the efficacy of second-line continued cetuximab.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Cetuximab/administração & dosagem , Neoplasias Colorretais/tratamento farmacológico , Camptotecina/administração & dosagem , Camptotecina/análogos & derivados , Estudos de Coortes , Neoplasias Colorretais/genética , Neoplasias Colorretais/patologia , Progressão da Doença , Esquema de Medicação , Fluoruracila/administração & dosagem , Humanos , Leucovorina/administração & dosagem , Masculino , Pessoa de Meia-Idade , Metástase Neoplásica , Compostos Organoplatínicos/administração & dosagem , Proteínas Proto-Oncogênicas p21(ras)/genética , Estudos Retrospectivos
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