Comparison of the inhibition potential of parthenolide and micheliolide on various UDP-glucuronosyltransferase isoforms.

Parthenolide (PTL) and micheliolide (MCL) are sesquiterpene lactones with similar structures, and both of them have been reported to exhibit multiple biochemical and pharmacological activities. This study aims to investigate the inhibition of these two compounds on the activity of UDP-glucuronosyltransferases (UGTs). In vitro incubation mixture for recombinant UGTs-catalyzed glucuronidation metabolism of 4-methylumbelliferone (4-MU) was utilized to investigate the inhibition potential. Inhibition kinetics (including inhibition type and parameters) were determined, and in silico docking was employed to elucidate the inhibition difference between PTL and MCL on UGT1A1. MCL showed no inhibition toward all the UGT isoforms, and PTL showed strong inhibition toward UGT1A1. The half-maximal inhibitory concentration (IC50) of PTL on the activity of UGT1A1 was determined to be 64.4 µM. Inhibition kinetics determination showed that PTL exerted noncompetitive inhibition toward UGT1A1, and the inhibition kinetic constant (Ki) was determined to be 12.1 µM. In silico docking method has been employed to show that hydrogen bonds between PTL and the activity cavity of UGT1A1 contributed to the stronger inhibition of PTL on the activity of UGT1A1 than MCL. In conclusion, PTL can more easily induce drug-drug interaction (DDI) with clinical drugs mainly undergoing UGT1A1-catalyzed glucuronidation.

Predicting the risk for colorectal cancer with personal characteristics and fecal immunochemical test.

We aimed to predict colorectal cancer (CRC) based on the demographic features and clinical correlates of personal symptoms and signs from Tianjin community-based CRC screening data.A total of 891,199 residents who were aged 60 to 74 and were screened in 2012 were enrolled. The Lasso logistic regression model was used to identify the predictors for CRC. Predictive validity was assessed by the receiver operating characteristic (ROC) curve. Bootstrapping method was also performed to validate this prediction model.CRC was best predicted by a model that included age, sex, education level, occupations, diarrhea, constipation, colon mucosa and bleeding, gallbladder disease, a stressful life event, family history of CRC, and a positive fecal immunochemical test (FIT). The area under curve (AUC) for the questionnaire with a FIT was 84% (95% CI: 82%-86%), followed by 76% (95% CI: 74%-79%) for a FIT alone, and 73% (95% CI: 71%-76%) for the questionnaire alone. With 500 bootstrap replications, the estimated optimism (<0.005) shows good discrimination in validation of prediction model.A risk prediction model for CRC based on a series of symptoms and signs related to enteric diseases in combination with a FIT was developed from first round of screening. The results of the current study are useful for increasing the awareness of high-risk subjects and for individual-risk-guided invitations or strategies to achieve mass screening for CRC.

Curcumin up regulates T helper 1 cells in patients with colon cancer.

The therapy for the advanced colon cancer (Cca) is unsatisfactory currently. To regulate the immune effector cell function has shown a positive effect on the treatment of advanced cancers. This study tests a hypothesis that administration with curcumin converts the Cca patient-derived regulatory T cells (Treg) to T helper (Th) 1 cells. In this study, a group of patients with advanced Cca was recruited into this study. The patients were treated with curcumin. The peripheral Tregs and Th1 cells were assessed by flow cytometry. The results showed that, after the curcumin therapy, the forkhead box protein (Foxp) 3 positive Treg frequency was markedly reduced, the frequency of Th1 cells was significantly increased in Cca patients. Treating with curcumin repressed the Foxp3 gene transcription in Tregs; the Tregs were then converted into Th1 cells. The results also revealed that Foxp3 bound T-bet to prevent IFN-γ expression in CD4+ T cells, which was abolished by treating with curcumin. In conclusion, the administration of curcumin can convert Tregs to Th1 cells via repressing Foxp3 expression and enhancing IFN-γ production.

Clarifying the debate on population-based screening for breast cancer with mammography: A systematic review of randomized controlled trials on mammography with Bayesian meta-analysis and causal model.

BACKGROUND: The recent controversy about using mammography to screen for breast cancer based on randomized controlled trials over 3 decades in Western countries has not only eclipsed the paradigm of evidence-based medicine, but also puts health decision-makers in countries where breast cancer screening is still being considered in a dilemma to adopt or abandon such a well-established screening modality. METHODS: We reanalyzed the empirical data from the Health Insurance Plan trial in 1963 to the UK age trial in 1991 and their follow-up data published until 2015. We first performed Bayesian conjugated meta-analyses on the heterogeneity of attendance rate, sensitivity, and over-detection and their impacts on advanced stage breast cancer and death from breast cancer across trials using Bayesian Poisson fixed- and random-effect regression model. Bayesian meta-analysis of causal model was then developed to assess a cascade of causal relationships regarding the impact of both attendance and sensitivity on 2 main outcomes. RESULTS: The causes of heterogeneity responsible for the disparities across the trials were clearly manifested in 3 components. The attendance rate ranged from 61.3% to 90.4%. The sensitivity estimates show substantial variation from 57.26% to 87.97% but improved with time from 64% in 1963 to 82% in 1980 when Bayesian conjugated meta-analysis was conducted in chronological order. The percentage of over-detection shows a wide range from 0% to 28%, adjusting for long lead-time. The impacts of the attendance rate and sensitivity on the 2 main outcomes were statistically significant. Causal inference made by linking these causal relationships with emphasis on the heterogeneity of the attendance rate and sensitivity accounted for the variation in the reduction of advanced breast cancer (none-30%) and of mortality (none-31%). We estimated a 33% (95% CI: 24-42%) and 13% (95% CI: 6-20%) breast cancer mortality reduction for the best scenario (90% attendance rate and 95% sensitivity) and the poor scenario (30% attendance rate and 55% sensitivity), respectively. CONCLUSION: Elucidating the scenarios from high to low performance and learning from the experiences of these trials helps screening policy-makers contemplate on how to avoid errors made in ineffective studies and emulate the effective studies to save women lives.

Prognostic factors in the patients with T2N0M0 colorectal cancer.

BACKGROUND: The 5-year survival rate of the patients with stage I colorectal cancer is about 90%; therefore, adjuvant therapy has not been recommended after radical resection; however, about 16-26% of T2N0M0 patients will be dead at 5 years despite radical curative resection. It indicated that there is a defined group of patients who are at high risk for relapse or metastasis despite radical operation. This study aimed to find the patients with T2N0M0 colorectal cancer at high risk for relapse or metastasis. METHODS: From January 1993 to December 2014, 812 patients with histologically confirmed stage T2N0M0 primary colorectal cancer treated by radical surgery with complete clinical follow-up data were eligible for this study. The medical records of all patients were collected and were retrospectively analyzed. Survival rates were calculated using Kaplan-Meier method, and survival cures were compared using the log-rank test. Cox proportional hazards model was used to analyze the significant factors defined in univariate test. RESULTS: The 5-year and 10-year overall survival rates were 81.9 and 67.7%, respectively. Male gender, old age, lymphovascular permeation, perineural invasion, and poor differentiation were associated with low cancer-specific survival rates in Kaplan-Meier analysis. Multivariate analyses revealed old age, lymphovascular permeation, perineural invasion, and poor differentiation as significant independent factors predicting worse prognosis (P < 0.05). CONCLUSIONS: Old age, lymphovascular permeation, perineural invasion, and poor differentiation are risk factors for the worse prognostic patients with T2N0M0 colorectal patients who would potential benefit from more aggressive therapy.

[Breviscapine listed on progress of new varieties and dosage form research].

Breviscapine, a flavone glucuronide, is a cardiovascular medicine extracted from a Chinese herb Erigeron breviscapinus. Modern pharmacological research shows breviscapine has a therapeutic effect on cardiovascular diseases such as cerebral thrombus,cerebral ischemia hemiparesis and platelet aggregation et al. However, its poor water solubility and low bioavailability in vivo severely restrict the clinical application. In this article, we reviewed the marketing preparations of breviscapine and its research progress on the new dosage forms.

[Relationship between colorectal adenocarcinoma with invasive micropapillary carcinoma component and lymph node metastasis].

OBJECTIVE: To investigate the relationship between colorectal adenocarcinoma with invasive micropapillary carcinoma (IMPC) component, lymphovascular invasion, and lymph node metastasis. METHODS: One hundred and thirty one cases of colorectal adenocarcinoma with invasive micropapillary carcinoma component were evaluated by H&E and immunohistochemical staining. The main pathological features, percentage of IMPC component, lymphovascular invasion, and lymph node metastasis were assessed and compared to 296 cases of conventional colorectal adenocarcinoma. RESULTS: The maximum diameter of the tumors of the IMPC group was significantly lower than the conventional group. The degree of differentiation, the lymph node metastatic rate, the average number of metastatic lymph nodes, the number of cases with lymphovascular tumor emboli were significantly higher in the IMPC group (P = 0.000). The rate of distant metastasis at operation was higher in the IMPC group (14.5%) compared to the conventional group (10.8%) even though statistical significance was not achieved (P = 0.278) . In IMPC group, as the IMPC component increased, the rate of lymph node metastasis also showed an increasing trend. The rate of lymph node metastasis were 53.0% (157/296) , 67.7% (42/62) and 85.5% (59/69) " respectively" for conventional adenocarcinoma, adenocarcinoma with ≤ 10% IMPC component and adenocarcinoma with > 10% IMPC component; the difference was statistically significant (P = 0.000). CONCLUSIONS: Compared to conventional colorectal adenocarcinomas, the colorectal carcinomas with IMPC component show a significantly higher rate of lymphovascular invasion, lymph node metastasis and distant metastasis. The percentage of IMPC component in colorectal adenocarcinoma is significantly correlated to the rate of lymph node metastasis. Therefore, presence of IMPC component and degree of tumor differentiation are predicting factors of lymph node metastasis.

Clinical and molecular analysis of hereditary non-polyposis colorectal cancer in Chinese colorectal cancer patients.

AIM: To analyze the frequency of hereditary non-polyposis colorectal cancer (HNPCC) in Chinese colorectal cancer (CRC) patients, and to discuss the value of microsatellite instability (MSI) and/or immunohistochemistry (IHC) for MSH2/MLH1 protein analysis as pre-screening tests in China. METHODS: The Amsterdam criteria I and II (clinical diagnosis) and/or germline hMLH1/hMSH2 mutations (genetic diagnosis) were used to classify HNPCC families. Genetic tests, including microsatellite instability, immunohistochemistry for MSH2/MLH1 proteins and hMSH2/hMLH1 genes, were performed in each proband. RESULTS: From July 2000 to June 2004, 1988 patients with colorectal cancer were analysed and 114 CRC patients (5.7%) from 48 families were categorized as having HNPCC, including 76 from 26 families diagnosed clinically and 38 from the other 22 families diagnosed genetically. The sensitivity and specificity of high MSI and IHC for predicting mutations were 100% and 54%, and 79% and 77%, respectively. CONCLUSION: The frequency of HNPCC is approximately 10% among all Chinese CRC cases. The MSI and IHC detections for hMSH2/hMLH1 proteins are reliable pre-screening tests for hMLH1/hMSH2 germline mutations in families suspected of having HNPCC.

[Clinical value of the sixth edition TNM stages analysing prognosis of colorectal cancer].

OBJECTIVES: To study the clinical value analyzing of colorectal cancer prognosis by the Sixth Edition TNM Stages. METHODS: 5481 cases with colorectal cancer and treated by operational methods, were collected. All the cases were separately staged by the Fifth Edition or Sixth Edition TNM Stages standards. The 5-year survival rates were analyzed by the life table method. RESULTS: The 5-year survival rates of the Fifth Edition TNM Stages of I, II, III and IV were 80.1%, 68.0%, 40.5% and 9.8% respectively. The 5-year survival rates of the Sixth Edition TNM Stages of II(A) and II(B) were 71.6% and 66.4% respectively, and of the stages III(A), III(B) and III(C) were 46.2%, 40.1% and 28.3% respectively. There were statistical differences among the sub-stages II and III, P < 0.05. CONCLUSION: The Sixth edition TNM Stages laid more stress on effect of the local infiltration depths and lymphatic metastasis in the prognosis of colorectal cancer, therefore, the stages were more fine, to analyze prognosis of the colorectal cancer were more precise. It is high clinical value for the individual complex treatment with every sub-stages.