NOX4 promotes tumor progression through the MAPK-MEK1/2-ERK1/2 axis in colorectal cancer

BACKGROUND Metabolic reprogramming plays a key role in cancer progression and clinical outcomes;however,the patterns and primary regulators of metabolic reprogramming in colorectal cancer(CRC)are not well understood.AIM To explore the role of nicotinamide adenine dinucleotide phosphate oxidase 4(NOX4)in promoting progression of CRC.METHODS We evaluated the expression and function of dysregulated and survival-related metabolic genes using Gene Ontology and Kyoto Encyclopedia of Genes and Genomes.Consensus clustering was used to cluster CRC based on dysregulated metabolic genes.A prediction model was constructed based on survival-related metabolic genes.Sphere formation,migration,invasion,proliferation,apoptosis and clone formation was used to evaluate the biological function of NOX4 in CRC.mRNA sequencing was utilized to explore the alterations of gene expression NOX4 over-expression tumor cells.In vivo subcutaneous and lung metastasis mouse tumor model was used to explore the effect of NOX4 on tumor growth.RESULTS We comprehensively analyzed 3341 metabolic genes in CRC and identified three clusters based on dysregulated metabolic genes.Among these genes,NOX4 was highly expressed in tumor tissues and correlated with worse survival.In vitro,NOX4 overexpression induced clone formation,migration,invasion,and stemness in CRC cells.Furthermore,RNA-sequencing analysis revealed that NOX4 overexpression activated the mitogen-activated protein kinase-MEK1/2-ERK1/2 signaling pathway.Trametinib,a MEK1/2 inhibitor,abolished the NOX4-mediated tumor progression.In vivo,NOX4 overexpression promoted subcutaneous tumor growth and lung metastasis,whereas trametinib treatment can reversed the metastasis.CONCLUSION Our study comprehensively analyzed metabolic gene expression and highlighted the importance of NOX4 in promoting CRC metastasis,suggesting that trametinib could be a potential therapeutic drugs of CRC clinical therapy targeting NOX4.

Development of a clinical nomogram for prediction of response to neoadjuvant chemotherapy in patients with advanced gastric cancer

BACKGROUND The efficacy of neoadjuvant chemotherapy(NAC)in advanced gastric cancer(GC)is still a controversial issue.AIM To find factors associated with chemosensitivity to NAC treatment and to provide the optimal therapeutic strategies for GC patients receiving NAC.METHODS The clinical information was collected from 230 GC patients who received NAC treatment at the Central South University Xiangya School of Medicine Affiliated Haikou Hospital from January 2016 to December 2020.Least absolute shrinkage and selection operator logistic regression analysis was used to find the possible predictors.A nomogram model was employed to predict the response to NAC.RESULTS In total 230 patients were finally included in this study,including 154 males(67.0%)and 76 females(33.0%).The mean age was(59.37±10.60)years,ranging from 24 years to 80 years.According to the tumor regression grade standard,there were 95 cases in the obvious response group(grade 0 or grade 1)and 135 cases in the poor response group(grade 2 or grade 3).The obvious response rate was 41.3%.Least absolute shrinkage and selection operator analysis showed that four risk factors significantly related to the efficacy of NAC were tumor location(P<0.001),histological differentiation(P=0.001),clinical T stage(P=0.008),and carbohydrate antigen 724(P=0.008).The C-index for the prediction nomogram was 0.806.The calibration curve revealed that the predicted value exhibited good agreement with the actual value.Decision curve analysis showed that the nomogram had a good value in clinical application.CONCLUSION A nomogram combining tumor location,histological differentiation,clinical T stage,and carbohydrate antigen 724 showed satisfactory predictive power to the response of NAC and can be used by gastrointestinal surgeons to determine the optimal treatment strategies for advanced GC patients.

Diagnostic value of circular free DNA for colorectal cancer detection

BACKGROUND Minimally invasive or noninvasive,sensitive and accurate detection of colorectal cancer(CRC)is urgently needed in clinical practice.AIM To identify a noninvasive,sensitive and accurate circular free DNA marker detected by digital polymerase chain reaction(dPCR)for the early diagnosis of clinical CRC.METHODS A total of 195 healthy control(HC)individuals and 101 CRC patients(38 in the early CRC group and 63 in the advanced CRC group)were enrolled to establish the diagnostic model.In addition,100 HC individuals and 62 patients with CRC(30 early CRC and 32 advanced CRC groups)were included separately to validate the model.CAMK1D was dPCR.Binary logistic regression analysis was used to establish a diagnostic model including CAMK1D and CEA.RESULTS To differentiate between the 195 HCs and 101 CRC patients(38 early CRC and 63 advanced CRC patients),the common biomarkers CEA and CAMK1D were used alone or in combination to evaluate their diagnostic value.The area under the curves(AUCs)of CEA and CAMK1D were 0.773(0.711,0.834)and 0.935(0.907,0.964),respectively.When CEA and CAMK1D were analyzed together,the AUC was 0.964(0.945,0.982).In differentiating between the HC and early CRC groups,the AUC was 0.978(0.960,0.995),and the sensitivity and specificity were 88.90%and 90.80%,respectively.In differentiating between the HC and advanced CRC groups,the AUC was 0.956(0.930,0.981),and the sensitivity and specificity were 81.30%and 95.90%,respectively.After building the diagnostic model containing CEA and CAMK1D,the AUC of the CEA and CAMK1D joint model was 0.906(0.858,0.954)for the validation group.In differentiating between the HC and early CRC groups,the AUC was 0.909(0.844,0.973),and the sensitivity and specificity were 93.00%and 83.30%,respectively.In differentiating between the HC and advanced CRC groups,the AUC was 0.904(0.849,0.959),and the sensitivity and specificity were 93.00%and 75.00%,respectively.CONCLUSION We built a diagnostic model including CEA and CAMK1D for differentiating between HC individuals and CRC patients.Compared with the common biomarker CEA alone,the diagnostic model exhibited significant improvement.

便秘状态下肠道菌群变化对脂代谢的影响

肠道菌群的稳定在维持机体健康中发挥重要作用,当便秘引起肠道菌群失衡时,它通过干扰胆汁酸(bile acids,BAs)的合成影响脂质消化、吸收过程;肠道菌群代谢物短链脂肪酸(short chain fatty acids,SCFAs)减少可破坏肠道黏膜屏障的完整性,且SCFAs的受体不能被激活,此外,氧化三甲胺(trimethylamine oxide,TMAO)产生量增多影响脂质代谢过程中关键酶的表达,进一步影响脂质转运、清除过程.本文就便秘状态下肠道菌群通过BAs、SCFAs、TMAO的变化介导脂代谢紊乱的机制作一综述.

Mechanism of exosomal microRNA-224 in development of hepatocellular carcinoma and its diagnostic and prognostic value

BACKGROUND Exosomes contain proteins, lipids, and biological molecules such as DNA and RNA. Nucleic acids in exosomes are a group of molecules that can act as biomarkers. Currently, there are many reports on exosomal microRNAs, which are ideal biomarkers for the early diagnosis of cancer. However, there are few reports on the role of exosomal microRNAs in the diagnosis and prognosis of hepatocellular carcinoma(HCC).AIM To understand the mechanism of exosomal microRNA-224(miR-224) in the development of HCC and evaluate its diagnostic and prognostic value.METHODS Cell culture and transfection of exosomal miRNA-224, real-time quantitative PCR, luciferase reporter assay, and other methods were used to find new biomarkers related to the development of HCC that can be used to diagnose HCC and predict HCC prognosis.RESULTSBy targeting glycine N-methyltransferase, incubating exosomes with miR-224 mimic resulted in a significant increase in cell proliferation compared to that of the control group, while incubation with the miR-224 inhibitor significantly reduced cell proliferation. The same results were obtained for the cell invasion assay. Serum exosomal miR-224 did have some ability to differentiate patients with HCC from healthy controls, with an area under the curve of 0.910, and HCC patients with higher serum exosomal miR-224 expression had lower overall survival.CONCLUSION Exosomal miR-224 is a tumor promotor and can be a marker of diagnosis and prognosis of HCC patients, however, its ability to distinguish liver diseases needs further verification.

Regorafenib combined with programmed cell death-1 inhibitor against refractory colorectal cancer and the platelet-to-lymphocyte ratio’s prediction on effectiveness

BACKGROUND The effectiveness of regorafenib plus programmed cell death-1(PD-1)inhibitor in treating microsatellite stable(MSS)metastatic colorectal cancer(mCRC)remains controversial.AIM To investigate the benefits of regorafenib combined with PD-1 inhibitor in treating MSS mCRC and explore indicators predicting response.METHODS This retrospective study included a total of 30 patients with microsatellite stable metastatic colorectal cancer treated with regorafenib combined with programmed cell death-1 inhibitor at Henan Provincial People’s Hospital between December 2018 and December 2020.During a 4-wk treatment cycle,regorafenib was performed for 3 continuous weeks.PD-1 inhibitor was intravenously injected starting on the first day of the oral intake of regorafenib.We reviewed tumor response,progression-free survival(PFS),overall survival,and treatment-related adverse events(TRAEs)and evaluated association between platelet-tolymphocyte ratio(PLR)and outcomes in this retrospective study.RESULTS Stable disease and progressive disease were found in 18(60.0%)and 12(40.0%)patients,respectively.The disease control rate was 60.0%.The median follow-up time was 12.0 mo,and median PFS was 3.4 mo[95%confidence interval(CI):2.2-4.6 mo].Of the 12 patients with progressive disease,10(83.3%)had liver metastasis before starting the combined treatment.Among the 18 patients with SD,10(55.6%)did not have liver metastases.One patient without liver metastases at baseline was found with a substantially prolonged PFS of 11.2 mo.The liver metastasis,the choice of programmed cell death-1 inhibitor other than nivolumab or pembrolizumab and previous exposure to regorafenib was’t associated with treatment outcome.The median PFS in the low-PLR group was 4.2 mo(95%CI:3.5-4.9 mo),compared with 2.8 mo(95%CI:1.4-4.2 mo)in the high-PLR group(P=0.005).The major TRAEs included hand-foot syndrome(33.3%),hypertension(23.3%),malaise(20.0%),and gastrointestinal reaction(16.7%).The incidence of grade 3 TRAEs was 13.3%(4/30),which comprised abnormal capillary proliferation(n=1),transaminase elevation(n=1),and hand-foot syndrome(n=2).No grade 4 or higher toxicity was observed.CONCLUSION Regorafenib combined with PD-1 inhibitor could lead to a longer PFS in some patients with MSS mCRC.The PLR might be a prediction of the patient response to this therapy.

肠道Cajal细胞数量对行吻合器经肛直肠切除术(STARR)的梗阻性排便综合征患者的预后和预测价值

目的:本研究旨在评估吻合器经肛直肠切除术(STARR)治疗梗阻性排便综合征(ODS)的功能学结果,并探讨肠道Cajal细胞(ICC)数量与STARR手术疗效的关系。方法:将50例行STARR手术的ODS患者的全层直肠标本,采用免疫组化方法检测直肠样本中的ICC细胞数量,并取20例来自直肠癌癌旁组织的直肠样本作为对照。收集排粪造影和直肠测压的功能学参数。结果:无论是在黏膜下层表面(SM)、肌纤维(IM)还是环形肌与纵形肌的肌间隙(MY)中,与对照标本相比,ODS直肠标本中的ICC细胞数量均显著减少(均P<0.05)。术前克利夫兰便秘评分(CCS)为24.2˘64.1,术后1、2、3、4和5年CCS评分均显著下降(均P<0.05)。术后3年,58.3%(28/48)的患者疗效满意(CCA≤10)。单因素分析显示,术前需手辅助排便(P=0.017)、ICC-MY细胞数量减少(P=0.067)、直肠感觉阈值增加(P=0.073)的ODS患者,术后功能学结果不良。多因素分析证实,ICC-MY细胞数量减少是术后不良功能学结果的独立预测因素(OR=0.097,95%CI:0.012-0.766)。结论:STARR手术治疗ODS总体疗效满意,但随时间推移,肛门功能会有所恶化。直肠标本中ICC细胞数量减少的患者术后肛门功能不良,提示术前对直肠进行全层组织学评估或可预测STARR手术的功能学结局.