Relationship of nonalcoholic fatty liver disease and obesity with risk of atherosclerotic cardiovascular disease / 中华全科医师杂志

Objective:To investigate the association of nonalcoholic fatty liver disease (NAFLD) and obesity with risk of atherosclerotic cardiovascular disease (ASCVD).Methods:A total of 1 486 individuals, including 1 051 males and 635 women aged (56.0±9.0) years, who underwent health check-up at the Union Hospital of Tongji Medical College, Huazhong University of Science and Technology from January 2020 to November 2021 were enrolled. The participants were divided into non-NAFLD group ( n=564), NAFLD without obesity group ( n=689), and NAFLD with obesity group ( n=233) according to the presence of NAFLD and body mass index. The general information, smoking history, alcohol consumption, medical history and results of physical examination, laboratory tests and liver ultrasound of participants were collected from the electronic medical record system. Body mass index≥28.0 kg/m 2 was defined as obesity, fatty liver was diagnosed by ultrasonography, and ASCVD risk was assessed according to the criteria of the Chinese guideline on the primary prevention of cardiovascular diseases( 2020). Multivariate logistic regression model was used to analyse the relationship of NAFLD and obesity with risk of ASCVD. Results:The proportions of individuals at high risk for ASCVD in the non-NAFLD group, the NAFLD without obesity group and the NAFLD with obesity group were 27.5%(155/564), 50.1%(345/689) and 61.8%(144/233), respectively, and the proportions of individuals at high ASCVD risk in the NAFLD without obesity group and the NAFLD with obesity group were higher than that in the non-NAFLD group (all P<0.05), and the proportion in the NAFLD with obesity group was higher than the NAFLD without obesity group ( P<0.05). Multivariate logistic regression analysis showed that NAFLD was significantly associated with a higher risk of ASCVD after correction for sex, alcohol consumption and alanine aminotransferase, and the association was stronger in the NAFLD with obesity, and the results were unchanged after further correction for uric acid, fasting glucose and systolic blood pressure (all P<0.001). Conclusion:NAFLD is strongly associated with the risk of ASCVD with or without obesity, and obesity may strengthen this association.

The Usefulness of Pretreatment MR-Based Radiomics on Early Response of Neoadjuvant Chemotherapy in Patients With Locally Advanced Nasopharyngeal Carcinoma.

The aim of this study was to explore the predictive role of pretreatment MRI-based radiomics on early response of neoadjuvant chemotherapy (NAC) in locoregionally advanced nasopharyngeal carcinoma (NPC) patients. Between January 2016 and December 2016, a total of 108 newly diagnosed NPC patients who were hospitalized in the Cancer Hospital of the University of Chinese Academy of Sciences were reviewed. All patients had complete data of enhanced MR of nasopharynx before treatment, and then received two to three cycles of TP-based NAC. After 2 cycles of NAC, enhanced MR of nasopharynx was conducted again. Compared with the enhanced MR images before treatment, the response after NAC was evaluated. According to the evaluation criteria of RECIST1.1, 108 cases were divided into two groups: 52 cases for the NAC-sensitive group and 56 cases for the NAC-resistance group. ITK-SNAP software was used to manually sketch and segment the region of interest (ROI) of nasopharyngeal tumor on the MR enhanced T1WI sequence image. The parameters were analyzed and extracted by using AI Kit software. ANOVA/MW test, correlation analysis, and LASSO were used to select texture features. We used multivariate logistic regressions to select texture features and establish a predictive model. The ROC curve was used to evaluate the efficiency of the predictive model. A total of 396 texture features were obtained by using feature calculation. After all features were screened, we selected two features including ClusterShade_angle135_offset4 and Correlation_AllDirection_offshe1_SD. Based on these two features, we established a predictive model by using multivariate logistic regression. The AUC of the two features used alone (0.804, 95% CI=0.6020.932; 0.762, 95% CI=0.5560.905) was smaller than the combination of these two features (0.905, 95% CI=0.7240.984, p=0.0005). Moreover, the sensitivity values of the two features used alone and the combined use were 92.9%, 51.7%, and 85.7%, respectively, while the specificity values were 66.7%, 91.7%, and 83.3%, respectively, in the early response of NAC for NPC. The predictive model based on MRI-enhanced sequence imaging could distinguish the sensitivity and resistance to NAC and provide new biomarkers for the early prediction of the curative effect in NPC patients.

Optimal induction chemotherapeutic regimen followed by concurrent chemotherapy plus intensity-modulated radiotherapy as first-line therapy for locoregionally advanced nasopharyngeal carcinoma.

For patients with locoregionally advanced nasopharyngeal carcinoma (NPC), induction chemotherapy (IC) regimens based on TPF (docetaxel, cisplatin, and 5-fluorouracil), TP (docetaxel and cisplatin), and GP (gemcitabine and cisplatin) have shown excellent survival outcomes as the first-line therapy; however, no trials comparing the efficacy and safety of TPF, TP, and GP have been reported. We report 2 phase II trials comparing the treatment outcomes and side effects of 3 different IC regimens followed by concurrent chemoradiotherapy in locoregionally advanced patients with NPC.A total of 206 locoregionally advanced patients with NPC treated with a combination treatment from January 2012 to January 2014 were enrolled in the 2 studies. The patients received TPF-, TP-, and GP-based IC regimens every 3 weeks, followed by intensity-modulated radiotherapy and concurrent therapy with cisplatin every 3 weeks.After a median follow-up duration of 47 months (10-60 months), the 3-year local recurrence-free survival, regional recurrence-free survival, distant metastases-free survival, progression-free survival, and overall survival rates were 96.4%, 100%, 87.7%, 86%, and 94.7% in the TPF arm; 91.7%, 95.9%, 91.9%, 85.2%, and 92% in the TP arm; 98.6%, 100%, 89.0%, 87.6%, and 89.2% in the GP arm. The survival differences among the 3 arms were not statistically significant (P > .05). The multivariate analysis demonstrated that the IC regimen was not an independent prognostic factor for any survival outcomes. The patients in the TP arm experienced significantly lower grade 3/4 toxicities than the patients in the other 2 arms.TP-based IC regimen has similar efficacy compared with TPF- and GP-based IC regimens; however, TP-based IC regimen has a lower toxicity profile.

Long-Term Use of Nimotuzumab in Combination With Intensity-Modulated Radiotherapy and Chemotherapy in the Treatment of Locoregionally Advanced Nasopharyngeal Carcinoma: Experience of a Single Institution.

In this retrospective review of a single institution's experience, the efficacy and safety of the long-term use of nimotuzumab in combination with intensity-modulated radiotherapy (IMRT) and chemotherapy in the treatment of locally advanced nasopharyngeal carcinoma (NPC) were studied. Between August 2008 and March 2014, 39 newly diagnosed patients with stages III-IV NPC were treated with IMRT, chemotherapy, and nimotuzumab. Twenty patients were diagnosed with stage III (51.3%), 14 with stage IVA (35.9%), and 5 with stage IVB (12.8%) disease. All patients received at least one cycle of cisplatin-based induction chemotherapy followed by IMRT and more than nine cycles of nimotuzumab at 200 mg/week. Acute and late radiation-related toxicities were graded according to the Acute and Late Radiation Morbidity Scoring Criteria of the Radiation Therapy Oncology Group. Accumulated survival was calculated according to the Kaplan-Meier method. The log-rank test was used to compare survival differences. With a median follow-up of 46 months (range, 22-86 months), the estimated 3-year local recurrence-free, regional recurrence-free, distant metastasis-free, progression failure-free, and overall survival rates were 92.1%, 89.7%, 82.5%, 77.6%, and 86.8%, respectively. Univariate analysis showed that clinical stage and the cycle of induction chemotherapy were related with prognosis. The median cycle for the addition of nimotuzumab was 12 weeks. Grade 3 radiation-induced mucositis was observed in 15.8% of the treated patients. No skin rash or infusion reaction was observed, which is distinctly different from what was reported in patients treated with nimotuzumab. The major toxicities observed were grades I-II mucositis and leukocytopenia. Long-term use of nimotuzumab plus IMRT showed promising outcomes in terms of locoregional control and survival, without increasing the incidence of radiation-related toxicities in patients.

The protective mechanisms of MEK1/2 inhibitor PD98059 on ox-LDL induced injury of HUVEC and the influence on the expression of LOX-1 / 重庆医学

Objective To investigate the protective mechanism of MEK1/2 inhibitor PD98059 on ox-LDL induced injury of human umbilical vein endothelial cells (HUVEC),and its influence on the expression of LOX-1.Methods HUVEC damage models were established by using ox-LDL and were treated with PD98059 later,divided into the negative control group,the ox-LDL group,the positive control group and the PD98059+ox-LDL group.The effect of inhibition of MEK1/2 on ox-LDL induced HUVEC damage was measured.Results Compared with the negative control group,the levels in the ox-LDL group of LOX-1,pMEK1/2,RhoA,ROCK1,ROCK2,TNF-α and IL-6 were increased significantly,the proliferations of HUVEC and the productions of NO were decreased (P＜0.05).Compared with the ox-LDL group,the levels in the positive control group and the PD98059+ox-LDL group of pMEK1/2,RhoA,ROCK1,ROCK2,TNF-α and IL-6 were decreased,the proliferation of HUVEC and the production of NO were increased (P＜0.05).Conclusion PD98059 inhibit the MEK1/2 signaling pathway to suppress the ox-LDL induced damage of HUVEC by decreasing the expression of LOX-1.

Association of the neoadjuvant chemotherapy cycle with survival outcomes in patients with locoregionally advanced nasopharyngeal carcinoma: a propensity-matched analysis.

Neoadjuvant chemotherapy (NAC) is widely used to treat locoregionally advanced nasopharyngeal carcinoma (NPC). To determine the optimal number of NAC cycles, we assessed the effect of NAC cycle on survival outcomes of locoregionally advanced NPC patients receiving NAC before concurrent chemotherapy and intensity-modulated radiotherapy. Clinical data from 1,188 non-metastatic NPC patients were retrospectively reviewed. All received ≥2 cycles of NAC added to concurrent chemoradiotherapy. Propensity score matching (PSM) was used to identify paired patients according to various covariates. In total, 297 pairs were selected. After a median follow-up time of 57 months (range: 7 to 104 months), the 5-year locoregional relapse-free survival, distant metastasis-free survival (DMFS), progression-free survival (PFS), and overall survival rates in patients treated with 2 cycles vs. 3 to 4 cycles of NAC were 91.3% vs. 87.2% (P=0.149), 93.3% vs. 88.5% (P=0.043), 88.7% vs. 81.7% (P=0.037), and 94.0% vs. 92.6% (P=0.266), respectively. On multivariate analysis, 2 cycles of NAC were associated with improved DMFS (hazard ratio, 0.499; P=0.038) and PFS (hazard ratio, 0.585; P=0.049). NAC cycle was an independent prognosticator of DMFS and PFS in univariate and multivariate analyses. Thus, 2 cycles of NAC appear sufficient, as additional cycles were not associated with added survival benefit for locoregionally advanced NPC.

Addition of 5-fluorouracil to first-line induction chemotherapy with docetaxel and cisplatin before concurrent chemoradiotherapy does not improve survival in locoregionally advanced nasopharyngeal carcinoma.

Although a multicenter, randomized study indicated that induction chemotherapy (IC) with docetaxel/cisplatin/fluorouracil (TPF) before concurrent chemoradiotherapy (CCRT) improves survival outcomes, it remains unclear whether TPF is the best IC regimen for treating locoregionally advanced nasopharyngeal carcinoma (NPC). Our aim was to compare the efficacy and toxicities of TPF vs. docetaxel/cisplatin (TP) IC followed by CCRT in patients with locoregionally advanced NPC. One hundred thirty-two patients with locoregionally advanced NPC received 21-day cycles of IC with either TPF or TP. Both were followed by intensity-modulated radiotherapy concurrent with the cisplatin treatment every 3 weeks. Three-year rates of locoregional relapse-free survival, distant metastasis-free survival, progression-free survival, and overall survival were respectively 96.4%, 87.7%, 86.0%, and 94.7% for patients in the TPF arm patients and 90.3%, 91.9%, 85.2%, and 92.0% for patients in the TP arm. There were no differences in survival between the two arms. Multivariate analysis revealed the IC regimen was not an independent prognostic factor for any survival outcome. However, patients in the TP arm experienced fewer grade 3/4 toxicities. In sum, IC with docetaxel and cisplatin is associated with similar efficacy and less toxicity than the TPF regimen. Addition of fluorouracil to docetaxel plus cisplatin IC is therefore not recommended for patients with locoregionally advanced NPC.

Gemcitabine/cisplatin induction chemotherapy before concurrent chemotherapy and intensity-modulated radiotherapy improves outcomes for locoregionally advanced nasopharyngeal carcinoma.

Addition of induction chemotherapy (IC) to concurrent chemoradiotherapy (CC) is an encouraging first-line treatment strategy for patients with locoregionally advanced nasopharyngeal carcinoma (NPC). We evaluated the clinical efficacy and toxicity of addition of gemcitabine plus cisplatin (GP) IC to intensity-modulated radiotherapy (IMRT) and CC for patients with locoregionally advanced NPC. At a median follow-up duration of 48 months (10-59 months), 4-year local relapse-free survival (LRFS) was 86.9%, regional relapse-free survival (RRFS) was 90.6%, distant metastasis-free survival (DMFS) was 79.8%, progression-free survival (PFS) was 77.0%, and overall survival (OS) was 81.9%. Univariate analysis revealed that T stage, N stage, clinical stage, and CC correlated with OS, while N stage and clinical stage correlated with PFS. In multivariate analysis, T4 was a prognostic indicator of poor OS and PFS, and N3 was a prognostic indicator of poor OS. Having received ≥ 2 cycles of IC was prognostic of better RRFS. During IC, grade 3-4 thrombocytopenia occurred in 10 patients, and grade 3-4 leukocytopenia was observed in 16 patients. Two patients developed mild liver dysfunction. These findings indicate that GP-based IC followed by CC has promising efficacy with acceptable toxicities.

Effect of hypoxia on forkhead box P3 expression in human oral squamous cell carcinoma cells and its mechanism / 吉林大学学报(医学版)

Objective:To investigate the effect of hypoxia on the expression of forkhead box P3 (FOXP3) in human oral squamous cell carcinoma (OSCC) cells,and to clarify its possible epigenetic mechanism.Methods:Two kinds of OSCC cell lines,FaDu and OECM-1,were cultured under normoxic or hypoxic conditions for 18 h.The relative expression levels of FOXP3 mRNA and protein in the cells were detected by Real-time RT-PCR and Western blotting method.The histone modification levels on the FOXP3 gene promoter,including acetylation of histone 3 lysine 4 (H3K4ac),trimethylation of histone 3 lysine 4 (H3K4me3) and lysine 27 (H3K27me3),were analyzed by Chromatin Immunocipitation (ChIP) and quantitative PCR (ChIP-qPCR).The relative expression levels of histone deacetylase 3 (HDAC3) mRNA and inhibitory rates of FOXP3 mRNA expression in the HDAC3-knockdown FaDu cells were investigated by Real-time qPCR and ChIP-qPCR.Results:Compared with normoxic condition,the relative expression levels of FOXP3 mRNA in FaDu and OECM-1 cells under hypoxic condition were decreased by 65.6% and 75.7% (P<0.01).The Western blotting results indicated that compared with normoxic condition,the expression levels of FOXP3 protein in FaDu and OECM-1 cells under hypoxic condition were decreased.The ChIP experiment results showed that compared with normoxic condition,the levels of H3K4ac and H3K4me3 on FOXP3 gene promoter in FaDu cells were decreased under hypoxic condition (P<0.01),while the H3K27me3 level was not changed.In HDAC3-knockdown FaDu cells,compared with control cells,the inhibitory rates of the expressions of H3K4ac and H3K4me3 on FOXP3 gene promoter under hypoxia condition were decreased (P<0.05),so did expressions the FOXP3 mRNA expression (P<0.05).Conclusion:Hypoxia could suppress the expression of FOXP3 by HDAC3-mediated down-regulation of H3K4ac on FOXP3 gene promoter in the human OSCC cells.