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1.
Cancer Med ; 2020 Jan 01.
Artigo em Inglês | MEDLINE | ID: mdl-31893575

RESUMO

Early identification of metastatic or recurrent colorectal cancer (CRC) patients who will be sensitive to FOLFOX (5-FU, leucovorin and oxaliplatin) therapy is very important. We performed microarray meta-analysis to identify differentially expressed genes (DEGs) between FOLFOX responders and nonresponders in metastatic or recurrent CRC patients, and found that the expression levels of WASHC4, HELZ, ERN1, RPS6KB1, and APPBP2 were downregulated, while the expression levels of IRF7, EML3, LYPLA2, DRAP1, RNH1, PKP3, TSPAN17, LSS, MLKL, PPP1R7, GCDH, C19ORF24, and CCDC124 were upregulated in FOLFOX responders compared with nonresponders. Subsequent functional annotation showed that DEGs were significantly enriched in autophagy, ErbB signaling pathway, mitophagy, endocytosis, FoxO signaling pathway, apoptosis, and antifolate resistance pathways. Based on those candidate genes, several machine learning algorithms were applied to the training set, then performances of models were assessed via the cross validation method. Candidate models with the best tuning parameters were applied to the test set and the final model showed satisfactory performance. In addition, we also reported that MLKL and CCDC124 gene expression were independent prognostic factors for metastatic CRC patients undergoing FOLFOX therapy.

2.
Int J Biol Sci ; 16(2): 228-238, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-31929751

RESUMO

The incidence of colorectal cancer is increasing, and cancer metastasis is one of the major causes of poor outcomes. BEX2 has been reported to be involved in tumor development in several types of cancer, but its role in metastatic colorectal cancer remains largely undefined. Herein, we demonstrated that BEX2 knockout resulted in enhanced migratory and metastatic potential in colorectal cancer cells both in vitro and in vivo, and re-expression of BEX2 in knockout cells could reverse the enhanced migratory capacity. RNA-Seq results indicated that the hedgehog signaling pathway was activated after BEX2 knockout; moreover, the hedgehog signaling inhibitors, GANT61 and GDC-0449 could reverse the migratory enhancement of BEX2-/- colorectal cancer cells. We also demonstrated that the nuclear translocation of Zic2 after BEX2 silencing could activate the hedgehog signaling pathway, while Zic2 knockdown abrogated the migratory enhancement of BEX2-/- cells and inhibited the hedgehog signaling pathway. In summary, our findings suggest that BEX2 negatively modulates the hedgehog signaling pathway by retaining Zic2 in the cytoplasm in colorectal cancer cells, thereby inhibiting migration and metastasis of colorectal cancer cells.

3.
J Cancer ; 10(26): 6594-6598, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31777588

RESUMO

Purpose: To investigate the accuracy of magnetic resonance imaging (MRI) in preoperative staging diagnosis for rectal cancer with multidisciplinary team (MDT) discussion. Methods: The retrospective study included 377 patients of rectal cancer with preoperative MRI staging from February 2015 to April 2018, in which 137 patients (36 received MDT discussion) received neoadjuvant therapy, 240 did not (97 received MDT discussion) and direct surgery was given. With postoperative pathological stage as the standard, the accuracy of MRI in preoperative staging for rectal cancer with MDT discussion was compared with non-MDT. Results: For direct surgery group, 21 out 97 (21.6%) patients changed their therapy strategy due to the change of the stage assessment after MDT. The accuracy of MRI for the diagnosis of preoperative N stage with MDT was significantly higher than those without MDT (56.2% vs. 42.1%, P=0.021). And for those without lymph node metastasis, the accuracy of MRI was higher after MDT (61.2% vs. 37.8%, P=0.009). For neoadjuvant therapy group, 7 out of 36 (19.4%) patients altered their therapy after MDT because of the changed stage. MDT improved the accuracy of restaging N stage with MRI (70.0% vs. 33.3%, P=0.003). The accuracy of MRI in staging T stage seemed not improved after MDT in both groups. Conclusions: In conclusion, MDT discussion increased the accuracy of MRI in preoperative staging diagnosis for rectal cancer. This mode could give a more accurate clinical stage of patients, which was in favor of choosing a preferable therapy strategy.

4.
Int J Cancer ; 2019 Nov 06.
Artigo em Inglês | MEDLINE | ID: mdl-31693169

RESUMO

The heterogeneities of colorectal cancer (CRC) lead to staging inadequately of patients' prognosis. Here, we performed a prognostic analysis based on the tumor mutational profile and explored the characteristics of the high-risk tumors. We sequenced 338 colorectal carcinomas as the training dataset, constructed a novel five-gene (SMAD4, MUC16, COL6A3, FLG and LRP1B) prognostic signature, and validated it in an independent dataset from The Cancer Genome Atlas (TCGA). Kaplan-Meier and Cox regression analyses confirmed that the five-gene signature is an independent predictor of recurrence and prognosis in patients with Stage III colon cancer. The mutant signature translated to an increased risk of death (hazard ratio = 2.45, 95% confidence interval = 1.15-5.22, p = 0.016 in our dataset; hazard ratio = 4.78, 95% confidence interval = 1.33-17.16, p = 0.008 in TCGA dataset). RNA and bacterial 16S rRNA sequencing of high-risk tumors indicated that mutations of the five-gene signature may lead to intestinal barrier integrity, translocation of gut bacteria and deregulation of immune response and extracellular related genes. The high-risk tumors overexpressed IL23A and IL1RN genes and enriched with cancer-related bacteria (Bacteroides fragilis,Peptostreptococcus, Parvimonas, Alloprevotella and Gemella) compared to the low-risk tumors. The signature identified the high-risk group characterized by gut bacterial translocation and upregulation of interleukins of the tumor microenvironment, which was worth further researching.

5.
Exp Ther Med ; 18(4): 2726-2730, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31572519

RESUMO

Megacolon is a congenital disorder. Adult congenital megacolon (ACM), also known as adult Hirschsprung's disease, is rare and frequently manifests as constipation. ACM is caused by the absence of ganglion cells in the submucosa or myenteric plexus of the bowel. Most patients undergo treatment of megacolon at a young age, but certain patients cannot be treated until they develop bowel obstruction in adulthood. Bowel obstruction in adults always occurs in complex clinical situations and it is frequently combined with comorbidities, including bowel tumors, volvulus, hernias, hypertension or diabetes mellitus. Surgical intervention is always required in such cases. To avoid recurrence, a sufficient amount of bowel should be removed, particularly the aganglionic segment. Furthermore, the patient's general physical condition should be considered pre-operatively by controlling parameters including blood pressure and blood glucose. In the present study, a case of ACM combined with fecal impaction and diabetic nephropathy was presented.

6.
BMC Cancer ; 19(1): 988, 2019 Oct 23.
Artigo em Inglês | MEDLINE | ID: mdl-31647032

RESUMO

BACKGROUND: Laparoscopic surgery, fast-track perioperative treatment and XELOX chemotherapy are effective strategies for shortening the duration of hospital stay for cancer patients. This trial aimed to clarify the safety and efficacy of the fast-track multidisciplinary treatment (FTMDT) model compared to conventional surgery combined with chemotherapy in Chinese colorectal cancer patients. METHODS: This trial was a prospective randomized controlled study with a 2 × 2 balanced factorial design and was conducted at six hospitals. Patients in group 1 (FTMDT) received fast-track perioperative treatment and XELOX adjuvant chemotherapy. Patients in group 2 (conventional treatment) received conventional perioperative treatment and mFOLFOX6 adjuvant chemotherapy. Subgroups 1a and 2a had laparoscopic surgery and subgroups 1b and 2b had open surgery. The primary endpoint was total length of hospital stay during treatment. RESULTS: A total of 374 patients were randomly assigned to the four subgroups, and 342 patients were finally analyzed, including 87 patients in subgroup 1a, 85 in subgroup 1b, 86 in subgroup 2a, and 84 in subgroup 2b. The total hospital stay of group 1 was shorter than that of group 2 [13 days, (IQR, 11-17 days) vs. 23.5 days (IQR, 15-42 days), P = 0.0001]. Compared to group 2, group 1 had lower surgical costs, fewer in-hospital complications and faster recovery (all P < 0.05). Subgroup 1a showed faster surgical recovery than that of subgroup 1b (all P < 0.05). There was no difference in 5-year overall survival between groups 1 and 2 [87.1% (95% CI, 80.7-91.5%) vs. 87.1% (95% CI, 80.8-91.4%), P = 0.7420]. CONCLUSIONS: The FTMDT model, which integrates laparoscopic surgery, fast-track treatment, and XELOX chemotherapy, was the superior model for enhancing the recovery of Chinese patients with colorectal cancer. TRIAL REGISTRATION: ClinicalTrials.gov: NCT01080547 , registered on March 4, 2010.

7.
Front Oncol ; 9: 497, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31263674

RESUMO

Background: Patients with rectal cancer who achieve pathologic complete response (pCR) after neoadjuvant chemoradiotherapy (nCRT) may have a better prognosis and may be eligible for non-operative management. The aim of this research was to identify variables for predicting pCR in rectal cancer patients after nCRT and to define clinical risk factors for poor outcome after pCR to nCRT and radical resection in rectal cancer patients. Methods: A retrospective review was performed using the Surveillance, Epidemiology, and End Results (SEER) database from 2004 to 2013. Non-metastatic rectal cancer patients who received radical resection after neoadjuvant chemoradiotherapy were included in this study. Multivariate analysis of the association between clinicopathological characteristics and pCR was performed, and a logistic regression model was used to identify independent predictors for pCR. A nomogram based on the multivariate logistics regression was built with decision curve analyses to evaluate the clinical usefulness. Results: A total of 6,555 patients were included in this study. The proportion of patients with pCR was 20.5% (n = 1,342). The nomogram based on multivariate logistic regression analysis showed that clinical T4 and N2 stages were the most significant independent clinical predictors for not achieving pCR, followed by mucinous adenocarcinoma and positive pre-treatment serum CEA results. The 3-year overall survival rate was 92.4% for those with pCR and 88.2% for those without pCR. Among all the pCR patients, mucinous adenocarcinoma patients had the worst survival, with a 3-year overall survival rate of 67.5%, whereas patients with common adenocarcinoma had an overall survival rate of 93.8% (P < 0.001). Univariate and multivariate analyses showed that histology and clinical N2 stage were independent risk factors. Conclusion: Mucinous adenocarcinoma, positive pre-treatment serum CEA results, and clinical T4 and N2 stages may impart difficulty for patients to achieve pCR. Mucinous adenocarcinoma and clinical N2 stage might be indicative of a prognostically unfavorable biological tumor profile with a greater propensity for local or distant recurrence and decreased survival.

8.
J Thorac Dis ; 11(3): 777-787, 2019 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-31019765

RESUMO

Background: The expression of CCL28 and its relationship with clinical outcomes remain unclear in the setting of heterogeneous breast cancer. The purpose of the current study was to identify the expression characteristics of chemokine CCL28 in breast cancer, with a focus on its prognostic relevance to different subtypes. Methods: First, we investigated the expression of CCL28 in 150 breast cancer patients immunohistochemically and assessed the impact of CCL28 on relapse-free survival (RFS) in the whole cohort and different clinical subtypes [defined by hormone receptor (HR), and HER-2 status] by univariate and multivariate analysis. Furthermore, the other two cohorts comprised of 863 patients from the Cancer Genome Atlas (TCGA) database and 1,764 patients from the Kaplan-Meier plotter database, respectively, were chosen to validate the prognostic values of CCL28 in breast cancer. Results: Those with positive CCL28 expression had improved RFS in luminal-like (HR positive, any HER-2 status) subtype (P=0.052) but had impaired RFS in triple-negative cases (P=0.019), after adjustment with tumor size and lymph node status. Consistently, multivariate analysis in the TCGA cohort revealed improved disease-free survival (DFS) among patients with high expression of CCL28 in luminal-like subtype (P=0.043) and decreased DFS in patients expressing high CCL28 in triple-negative cases (P=0.010). The subsequent analysis of the Kaplan-Meier plotter cohort also demonstrated that CCL28 was a favorable prognostic factor for luminal-like cases [luminal A (P<0.001) and luminal B (P=0.031)], but a poor prognostic indicator for the patients with triple-negative phenotype (P<0.001). Conclusions: CCL28 was a favorable prognostic factor for luminal-like cases and detrimental for triple-negative subtype, indicating that the same chemokine may play different or even opposite roles in the recurrence and metastasis of different molecular subtypes of breast cancer.

9.
J Cancer ; 10(6): 1520-1527, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31031862

RESUMO

Purpose: The prevalence of esophageal NECs is rising, but to date, no studies have compared its clinicopathological characteristics to those of esophageal ACs and SCCs from the same period. Patients and methods: A 10-year population-based retrospective cohort study was conducted with the Surveillance, Epidemiology, and End Results Program database. Statistical analyses were performed using Intercooled Stata 12.0 software. Results: A total of 17,196 eligible patients with esophageal tumors, including 246 NECs, 6,102 SCCs and 10,848 ACs, were analyzed. ACs showed an obviously higher prevalence than the other two tumor types, and the prevalence of NECs was increasing. NECs were associated with an obviously worse survival than ACs (log-rank test, P<0.01). Most NECs were poorly differentiated and had an obviously higher percentage of metastasis. NECs and ACs often metastasized to the liver (29.41% and 23.11%, respectively), while SCCs typically metastasized to the lung (15.84%) and distant lymph nodes (15.37%). We divided the patients into two groups for further analysis according to the metastasis status. For NECs, no benefit was obtained by surgery in metastatic disease. For SCCs and ACs, surgery of the primary sites produced survival benefits in both groups, but the benefits of lymphadenectomy and metastasis dissection need further study. Conclusion: NECs of the esophagus have the worst prognosis compared to SCCs and ACs from the same period. Radical surgery provides limited benefits to patients diagnosed with NECs, so systemic treatments should be considered instead of surgical procedures. A unique guideline with a new staging and grading system for esophageal NECs is urgently needed.

10.
Int J Cancer ; 145(5): 1395-1407, 2019 09 01.
Artigo em Inglês | MEDLINE | ID: mdl-30828790

RESUMO

Metastasis of colorectal cancer (CRC) is the leading cause of CRC-associated mortality. Angiogenin (ANG), a member of the ribonuclease A superfamily, not only activates endothelial cells to induce tumor angiogenesis, but also targets tumor cells to promote cell survival, proliferation and/or migration. However, its clinical significance and underlying mechanism in CRC metastasis are still largely unknown. Here, we reported that ANG was upregulated in CRC tissues and associated with metastasis in CRC patients. We then revealed that ANG enhanced CRC growth and metastasis in both in vitro and in vivo systems. Intriguingly, we characterized a bunch of tRNA-derived stress-induced small RNAs (tiRNAs), produced through ANG cleavage, that was enriched in both CRC tumor tissues and highly metastatic cells, and functioned in ANG-promoted CRC metastasis. Moreover, higher level of a 5'-tiRNA from mature tRNA-Val (5'-tiRNA-Val) was observed in CRC patients and was correlated with tumor metastasis. Taken together, we propose that a novel ANG-tiRNAs-cell migration and invasion regulatory axis promotes CRC metastasis, which might be of potential target for CRC diagnosis and treatment.

11.
J Biomed Inform ; 92: 103117, 2019 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-30738948

RESUMO

The utility of a prediction model depends on its generalizability to patients drawn from different but related populations. We explored whether a semi-supervised learning model could improve the generalizability of colorectal cancer (CRC) risk prediction relative to supervised learning methods. Data on 113,141 patients diagnosed with nonmetastatic CRC from 2004 to 2012 were obtained from the Surveillance Epidemiology End Results registry for model development, and data on 1149 patients from the Second Affiliated Hospital, Zhejiang University School of Medicine, who were diagnosed between 2004 and 2011, were collected for generalizability testing. A clinical prediction model for CRC survival risk using a semi-supervised logistic regression method was developed and validated to investigate the model discrimination, calibration, generalizability, interpretability and clinical usefulness. Rigorous model performance comparisons with other supervised learning models were performed. The area under the curve of the logistic membership model revealed a large heterogeneity between the development cohort and validation cohort, which is typical of generalizability studies of prediction models. The discrimination was good for all models. Calibration was poor for supervised learning models, while the semi-supervised logistic regression model exhibited a good calibration on the validation cohort, which indicated good generalizability. Clinical usefulness analysis showed that semi-supervised logistic regression can lead to better clinical outcomes than supervised learning methods. These results increase our current understanding of the generalizability of different models and provide a reference for predictive model development for clinical decision-making.

12.
J Hematol Oncol ; 12(1): 16, 2019 02 14.
Artigo em Inglês | MEDLINE | ID: mdl-30764882

RESUMO

The lungs are the second most common site of metastasis for colorectal cancer (CRC) after the liver. Rectal cancer is associated with a higher incidence of lung metastases compared to colon cancer. In China, the proportion of rectal cancer cases is around 50%, much higher than that in Western countries (nearly 30%). However, there is no available consensus or guideline focusing on CRC with lung metastases. We conducted an extensive discussion and reached a consensus of management for lung metastases in CRC based on current research reports and the experts' clinical experiences and knowledge. This consensus provided detailed approaches of diagnosis and differential diagnosis and provided general guidelines for multidisciplinary therapy (MDT) of lung metastases. We also focused on recommendations of MDT management of synchronous lung metastases and initial metachronous lung metastases. This consensus might improve clinical practice of CRC with lung metastases in China and will encourage oncologists to conduct more clinical trials to obtain high-level evidences about managing lung metastases.

13.
J Cell Physiol ; 2019 Jan 29.
Artigo em Inglês | MEDLINE | ID: mdl-30697742

RESUMO

Colorectal cancer (CRC) is a leading cause of cancer death. This study was conducted to investigate the functions and mechanisms of Zyxin (ZYX) in CRC. Multiomics analysis associated ZYX with CRC metastasis. ZYX expression levels were increased in human CRC tissues and related to shorter recurrence-free survival. Knockdown of ZYX expression resulted in inhibition of cell growth, invasion, and migration in vitro and in vivo. Comprehensive analysis of gene microarray analysis showed that ZYX may activate the pathway of NUPR1 and JNK, inhibit CST5, regulate focal adhesion (FA), and affect epithelial-mesenchymal transition in CRC cells. Results of gene microarray and membrane protein isobaric tags with relative and absolute quantitation labeling mass spectrometry found ten differentially expressed genes, which were associated with ZYX activity. Furthermore, real-time polymerase chain reaction was used to validate the expression patterns of selected genes in the integrative analysis. Taken together, our findings provide the first evidence that decreased expression level of ZYX impairs CRC cell proliferation and metastasis probably via the FA pathway.

14.
Cancer Biol Ther ; 20(4): 391-396, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30307354

RESUMO

BACKGROUND: Substantial progress has been made in metastatic colorectal cancer (mCRC) treatment, but there is still a fraction of patients cannot find any effective therapeutic strategy after guideline-recommended standard chemotherapy and molecular targeted therapy. CASE PRESENTATION: Here we present a KRAS/NRAS/BRAF wild-type mCRC patient who has been previously treated with FOLFIRI (fluorouracil, leucovorin, and irinotecan), XELOX (capecitabine and oxaliplatin), cetuximab and bevacizumab, and then received the next generation sequencing (NGS) and whose metastatic subcutaneous nodule was resected to generate patient-derived xenograft (PDX) models. The NGS revealed HER-2 amplification as well as an activating mutation S310F and PDX models tested several drugs finding that afatinib was the optimal agent with notable efficacy and well tolerance among 6 regimens. Therefore, this patient started to take afatinib orally and achieved 3 months progression-free survival (PFS) and relief of clinical symptoms without severe adverse effects. CONCLUSIONS: NGS and PDX models have great significance for precision and individualized medicine in the mCRC treatment, especially for patients whose diseases have been progressed after multiline standard therapies.

15.
Eur Radiol ; 29(3): 1114-1123, 2019 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-30255251

RESUMO

OBJECTIVE: By evaluating extent of tumour enhancement on preoperative contrast-enhanced MDCT, we aimed to establish an imaging-based model to predict cancer-specific survival in stage I-III colon cancer. METHODS: A total of 548 stage I-III colon cancer patients who underwent curative resection from 2007 to 2013 were retrospectively included and divided into primary cohort and validation cohort according to admission time. The attenuation coefficient of each colon cancer was measured on the workstation by drawing the ROI in CT images. The enhancement ratio was calculated using maximum tumour attenuation value in triphasic MDCT scanning divided by the minimum. Patients were divided into low/high-enhancement groups according to the optimal cut-off value derived from time-dependent ROC curve. Kaplan-Meier method and COX regression analysis were adopted to evaluate prognostic value of variables. A nomogram for prognosis was conducted on the basis of a multivariate Cox proportional hazard model. RESULTS: No significant differences were observed in age, sex, pTNM stage, perioperative chemoradiotherapy, serum CEA, tumour size, tumour localisation and histologic type between low- and high-enhancement groups. The high-enhancement group had a significantly shorter cancer-specific survival rate (69.5%) than the low-enhancement group (85.9%) (p < 0.001). Subgroup analysis indicated that high-enhancement state was closely associated with increased risk of colon cancer mortality in stage I (p = 0.033), stage II (p = 0.002) and stage III (p = 0.014). Cox regression analysis indicated the extent of enhancement was an independent prognostic factor (HR 2.258, 95% CI 1.476-3.455; p < 0.001). CONCLUSIONS: The extent of tumour enhancement on MDCT can serve as a potential risk factor for stage I-III colon cancer. KEY POINTS: • Survival rates of stage I-III colon cancer vary widely even within the same stage. • Prognostic value of the extent of tumour enhancement on MDCT was assessed. • The high-enhancement group had a significantly shorter cancer-specific survival rate.


Assuntos
Colo/diagnóstico por imagem , Neoplasias do Colo/diagnóstico , Aumento da Imagem/métodos , Tomografia Computadorizada Multidetectores/métodos , Estadiamento de Neoplasias/métodos , Adulto , Idoso , China/epidemiologia , Estudos de Coortes , Neoplasias do Colo/mortalidade , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Prognóstico , Curva ROC , Estudos Retrospectivos , Fatores de Risco , Taxa de Sobrevida/tendências
16.
J Cell Physiol ; 234(4): 3675-3684, 2019 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-30256389

RESUMO

Hepatocyte nuclear factor 6 (HNF6), as a transcription factor, has been reported to be involved in cell proliferation, carcinogenesis, and tumor metastasis. Here, we demonstrated the role of HNF6 in tumor growth and liver metastasis in colorectal cancer (CRC). Through bioinformatics and clinical samples analysis, we found HNF6 messenger RNA was upregulated both in CRC primary sites and liver metastases, and its high expression indicated poor survival in CRC patients. In vitro studies confirmed that HNF6 promoted cell proliferation and colony formation. What is more, in mouse models, the xenografts grew significantly faster and liver metastasis rate was nearly 45% higher in mice injected with HNF6-overexpressing cells. Further mechanism exploration showed that HNF6 expression affected cell adhesion and conferred resistance to anoikis in CRC cells. Taken together, HNF6 expression was upregulated in CRC and closely correlated with poor survival. HNF6 promoted CRC cell proliferation and tumor growth, and may contribute to liver metastasis via conferring cell resistance to anoikis.

17.
Cancer Manag Res ; 11: 95-105, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30588113

RESUMO

Objectives: Deguelin, a rotenoid extracted from Mundulea sericea (Leguminosae), exhibits antitumor effects on several types of human cancers. Due to the limited studies of deguelin on colorectal cancer (CRC), the present study was designed to investigate the antitumor effect of deguelin and to explore the underlying mechanism in CRC. Materials and methods: Cell viability was assessed by the cell counting kit-8 (CCK-8) assay, and cell apoptosis was determined by the annexin v-propidium iodide staining using flow cytometry and Western blot in CRC cell lines after incubation with deguelin. The antitumor effect of deguelin was further evaluated in tumor xenograft models. Moreover, SB203580, a specific inhibitor of p38 MAPK, was used to confirm the involvement of p38 MAPK pathway in deguelin-induced apoptosis. Results: Deguelin significantly inhibited cell proliferation and induced apoptosis in CRC cell lines (SW620 and RKO) in a time-dependent and dose-dependent manner. Western blot analysis also showed that the expression of proapoptotic proteins (cleaved caspase 3 and cleaved PARP) was upregulated, while that of antiapoptotic proteins (Bcl-2 and survivin) was downregulated after deguelin treatment in CRC cell lines. Moreover, oral administration of deguelin significantly suppressed tumor growth and induced apoptosis in subcutaneous xenograft mouse models without obvious toxicity. Additionally, Western blot revealed that deguelin-induced apoptosis might be regulated by the p38 MAPK pathway and inhibition of p38 MAPK could attenuate deguelin-induced proliferative inhibition and apoptosis in CRC cells. Conclusion: Collectively, these results demonstrated that deguelin inhibited CRC cell growth by inducing apoptosis via activation of p38 MAPK pathway.

18.
BMC Cancer ; 18(1): 1084, 2018 Nov 08.
Artigo em Inglês | MEDLINE | ID: mdl-30409119

RESUMO

BACKGROUND: An increasing number of studies have identified spatial differences in colorectal cancer survival. However, little is known about the spatially varying effects of predictors in survival prediction modeling studies of colorectal cancer that have focused on estimating the absolute survival risk for patients from a wide range of populations. This study aimed to demonstrate the spatially varying effects of predictors of survival for nonmetastatic colorectal cancer patients. METHODS: Patients diagnosed with nonmetastatic colorectal cancer from 2004 to 2013 who were followed up through the end of 2013 were extracted from the Surveillance Epidemiology End Results registry (Patients: 128061). The log-rank test and the restricted mean survival time were used to evaluate survival outcome differences among spatial clusters corresponding to a widely used clinical predictor: stage determined by AJCC 7th edition staging system. The heterogeneity test, which is used in meta-analyses, revealed the spatially varying effects of single predictors. Then, considering the above predictors in a standard survival prediction model based on spatially clustered data, the spatially varying coefficients of these models revealed that some covariate effects may not be constant across the geographic regions of the study. Then, two types of survival prediction models (a statistical model and a machine learning model) were built; these models considered the predictors and enabled survival prediction for patients from a wide range of geographic regions. RESULTS: Based on univariate and multivariate analysis, some prognostic factors, such as "TNM stage", "tumor size" and "age at diagnosis," have significant spatially varying effects among different regions. When considering these spatially varying effects, machine learning models have fewer assumption constraints (such as proportional hazard assumptions) and better predictive performance compared with statistical models. Upon comparing the concordance indexes of these two models, the machine learning model was found to be more accurate (0.898[0.895,0.902]) than the statistical model (0.732 [0.726, 0.738]). CONCLUSIONS: Based on this study, it's recommended that the spatially varying effect of predictors should be considered when building survival prediction models involving large-scale and multicenter research data. Machine learning models that are not limited by the requirement of a statistical hypothesis are promising alternative models.


Assuntos
Neoplasias Colorretais/mortalidade , Adulto , Idoso , Idoso de 80 Anos ou mais , Neoplasias Colorretais/epidemiologia , Neoplasias Colorretais/patologia , Feminino , Humanos , Estimativa de Kaplan-Meier , Aprendizado de Máquina , Masculino , Pessoa de Meia-Idade , Análise Multivariada , Estadiamento de Neoplasias , Prognóstico , Modelos de Riscos Proporcionais , Programa de SEER , Análise Espacial , Estados Unidos/epidemiologia
19.
Crit Rev Oncog ; 23(3-4): 219-234, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30311576

RESUMO

Epstein-Barr virus (EBV)-associated nasopharyngeal carcinoma (NPC) is one of the most common head and neck malignancies in southern China and Southeast Asia. Unfortunately, 70% of NPC patients have locally advanced disease at the first diagnosis. Radiotherapy alone and concurrent chemoradiotherapy are important treatment approaches for NPC, but they have a limited effect on patients with locally advanced or distantly metastatic disease. 1-5 Nevertheless, the unique immune environment of the EBV-associated NPC provides rational targets for immunotherapy. Diverse types of immunotherapies are actively being studied, including adoptive immunotherapy, therapeutic vaccines, immune checkpoint inhibitors, lytic-induction therapy, and viral immunotherapy. Specifically, adoptive immunotherapy with lymphocyte infusion was well tolerated and effective in 71.4% of patients combined with first-line chemotherapy. Several therapeutic vaccines and PD-1/PD-L1 pathway checkpoint inhibitors have shown promising clinic outcomes at phase I/II clinical trials. Moreover, EBV-lytic inducing therapy and viral immunotherapy for NPC are also being investigated. In this review, we summarized the current status, advantages, and disadvantages of each immunotherapy for EBV-associated NPC, which may shed light on developing safer and more effective treatment modalities in the future.


Assuntos
Infecções por Vírus Epstein-Barr/complicações , Infecções por Vírus Epstein-Barr/virologia , Herpesvirus Humano 4 , Imunoterapia , Carcinoma Nasofaríngeo/etiologia , Carcinoma Nasofaríngeo/terapia , Animais , Vacinas Anticâncer/imunologia , Vacinas Anticâncer/uso terapêutico , Transformação Celular Viral , Células Matadoras Induzidas por Citocinas/imunologia , Células Matadoras Induzidas por Citocinas/metabolismo , Infecções por Vírus Epstein-Barr/imunologia , Herpesvirus Humano 4/fisiologia , Interações Hospedeiro-Patógeno/imunologia , Humanos , Imunomodulação , Imunoterapia/efeitos adversos , Imunoterapia/métodos , Imunoterapia Adotiva , Linfócitos do Interstício Tumoral/imunologia , Linfócitos do Interstício Tumoral/metabolismo , Terapia de Alvo Molecular/métodos , Carcinoma Nasofaríngeo/diagnóstico
20.
J Biomed Inform ; 86: 1-14, 2018 10.
Artigo em Inglês | MEDLINE | ID: mdl-30103028

RESUMO

BACKGROUND AND OBJECTIVE: Clinical prognosis prediction plays an important role in clinical research and practice. The construction of prediction models based on electronic health record data has recently become a research focus. Due to the lack of external validation, prediction models based on single-center, hospital-specific datasets may not perform well with datasets from other medical institutions. Therefore, research investigating prognosis prediction model construction based on a collaborative analysis of multi-center electronic health record data could increase the number and coverage of patients used for model training, enrich patient prognostic features and ultimately improve the accuracy and generalization of prognosis prediction. MATERIALS AND METHODS: A web service for individual prognosis prediction based on multi-center clinical data collaboration without patient-level data sharing (POPCORN) was proposed. POPCORN focuses on solving key issues in multi-center collaborative research based on electronic health record systems; these issues include the standardization of clinical data expression, the preservation of patient privacy during model training and the effect of case mix variance on the prediction model construction and application. POPCORN is based on a multivariable meta-analysis and a Bayesian framework and can construct suitable prediction models for multiple clinical scenarios that can effectively adapt to complex clinical application environments. RESULTS: POPCORN was validated using a joint, multi-center collaborative research network between China and the United States with patients diagnosed with colorectal cancer. The performance of the models based on POPCORN was comparable to that of the standard prognosis prediction model; however, POPCORN did not expose raw patient data. The prediction models had similar AUC, but the BMA model had the lowest ECI across all prediction models, indicating that this model had better calibration performance than the other models, especially for patients in Chinese hospitals. CONCLUSIONS: The POPCORN system can build prediction models that perform well in complex clinical application scenarios and can provide effective decision support for individual patient prognostic predictions.


Assuntos
Neoplasias Colorretais/diagnóstico , Neoplasias Colorretais/epidemiologia , Sistemas de Apoio a Decisões Clínicas , Registros Eletrônicos de Saúde , Internet , Acesso à Informação , Idoso , Algoritmos , Teorema de Bayes , Calibragem , China , Diagnóstico por Computador , Feminino , Humanos , Disseminação de Informação , Cooperação Internacional , Masculino , Pessoa de Meia-Idade , Probabilidade , Prognóstico , Reprodutibilidade dos Testes , Estados Unidos
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