Predictive Nomogram for the Prediction of Early Recurrence of Colorectal Cancer.

AIM: The prognosis of colorectal cancer (CRC) individuals after curative resection is not satisfactory due to the early recurrence. We sought to identify the affecting features of early recurrence in CRC patients. METHODS: A total of 3500 CRC patients underwent curative resection were retrospectively incorporated into our study. Among them, 246 patients exhibited tumor recurrence: 121 had early recurrence (≤1 year after operation) and 125 had late recurrence (>1 year after operation). A total of 246 CRC patients with recurrence were randomly assigned into the training group (N=177) or validation group (N=69) based on the ratio of 7:3. LASSO COX regression and support vector machine (SVM) were utilized to screen for the significant clinical indexes associated with the presence of early recurrence. Recurrent nomogram was created based on the above informative parameters to predict the probability of early recurrence. RESULTS: Proportion of advanced TNM stage, platelet count, systemic immune-inflammation index (SII), mean corpuscular hemoglobin concentration (MCHC), CA-199, CA-125, lactate dehydrogenase, total bile acid (TBA), urea nitrogen were significantly higher in early recurrence group compared with that in late recurrence group. Results from LASSO COX regression and support vector machine (SVM) revealed that TNM stage, CA-199, CA125, SII and TBA were strong predictors for the presence of early recurrence among postoperative CRC patients in the training group. The recurrent nomogram based on the five predictors exhibited good predictive performance as calculated by C-index (0.846, 95% CI 0.789-0.902 in the training group and 0.799, 95% CI 0.697-0.902 in the validation group) for the prediction of early recurrence. Moreover, the recurrent nomogram exhibited not only encouraging calibration ability, but also great clinical utility both in the training group and validation group. CONCLUSION: TNM stage, CA-199, CA125, SII and TBA were closely correlated with the presence of early recurrence of CRC patients. The recurrent nomogram held well predictive ability for the identification of CRC patients with early recurrence.

Prognostic Value of Glucose-to-Lymphocyte Ratio in Critically Ill Patients with Acute Pancreatitis.

BACKGROUND: Glucose metabolism and systemic inflammation have been associated with prognosis in acute pancreatitis (AP) patients. However, the possible value as a prognostic marker of the glucose-to-lymphocyte ratio (GLR) has not been evaluated in critically ill patients with AP. METHODS: This study included 1,133 critically ill patients with AP from the Medical Information Mart for Intensive Care-IV (MIMIC-IV) database, who were randomly divided into the training cohort (n=806) and the validation cohort (n=327) at a ratio of 7:3. X-tile software was used to determine the optimal cut-off values for GLR. Area under the curve (AUC) analysis was performed to compare the performance between GLR and other blood-based inflammatory biomarkers. Univariate and multivariate Cox regression analyses were applied to select prognostic factors associated with in-hospital mortality. A nomogram model was developed based on the identified prognostic factors and the validation cohort was used to further validate the nomogram. RESULTS: The optimal cut-off value for GLR was 0.9. The ROC analyses showed that the discrimination abilities of GLR were better than other blood-based inflammatory biomarkers. Multivariate Cox regression analysis demonstrated that age, platelet, albumin, bilirubin, Sequential Organ Failure Assessment (SOFA) score, and GLR are independent predictors of poor overall survival in the training cohort and were incorporated into the nomogram for in-hospital mortality as independent factors. The nomogram exhibited better discrimination with C-indexes in the training cohort and the validation cohort of 0.886 (95% CI=0.849-0.922) and 0.841 (95% CI=0.767-0.915), respectively. The calibration plot revealed an adequate fit of the nomogram for predicting the risk of in-hospital mortality in both sets. CONCLUSION: As an easily available biomarker, GLR can independently predict the in-hospital mortality of critically ill patients with AP. The nomogram combining GLR with other significant features exerted favorable predictive performance for in-hospital mortality.

CEP-33779 antagonizes ATP-binding cassette subfamily B member 1 mediated multidrug resistance by inhibiting its transport function.

The overexpression of ATP-binding cassette (ABC) transporters often leads to the development of multidrug resistance (MDR), which is the major factor contributing to the failure of chemotherapy. The objective of this study was to investigate the enhancement of CEP-33779, a small-molecule inhibitor of Janus kinase 2 (JAK2), on the efficacy of conventional chemotherapeutic agents in MDR cells with overexpression of P-glycoprotein (ABCB1), multidrug resistance-associated protein 1 (ABCC1) and breast cancer resistance protein (ABCG2). Our results showed that CEP-33779, at nontoxic concentrations, significantly sensitized ABCB1 overexpressing MDR cells to its anticancer substrates. CEP-33779 significantly increased intracellular accumulation and decreased the efflux of doxorubicin by inhibiting the ABCB1 transport function. Furthermore, CEP-33779 did not alter the expression of ABCB1 both at protein and mRNA levels but did stimulate the activity of ABCB1 ATPase. CEP-33779 was predicted to bind within the large hydrophobic cavity of homology modeled ABCB1. In addition, the down-regulation of JAK2 by shRNA altered neither the expression of ABCB1 nor the cytotoxic effect of chemotherapeutic agents in ABCB1-overexpressing cells. Significantly, CEP-33779 enhanced the efficacy of vincristine against the ABCB1-overexpressing and drug resistant KBv200 cell xenograft in nude mice. In conclusion, we conclude that CEP-33779 enhances the efficacy of substrate drugs in ABCB1-overexpressing cells by directly inhibiting ABCB1 transport function. The findings encouraged to further study on the combination therapy of CEP-33779 with conventional chemotherapeutic agents in ABCB1 mediated-MDR cancer patients.

UMMS-4 enhanced sensitivity of chemotherapeutic agents to ABCB1-overexpressing cells via inhibiting function of ABCB1 transporter.

Multidrug resistance (MDR) mediated by ATP-binding cassette (ABC) transporters through efflux of antineoplastic agents from cancer cells is a major obstacle to successful cancer chemotherapy. The inhibition of these ABC transporters is thus a logical approach to circumvent MDR. There has been intensive research effort to design and develop novel inhibitors for the ABC transporters to achieve this goal. In the present study, we evaluated the ability of UMMS-4 to modulate P-glycoprotein (P-gp/ABCB1)-, breast cancer resistance protein (BCRP/ABCG2)- and multidrug resistance protein (MRP1/ABCC1)-mediated MDR in cancer cells. Our findings showed that UMMS-4, at non-cytotoxic concentrations, apparently circumvents resistance to ABCB1 substrate anticancer drugs in ABCB1-overexpressing cells. When used at a concentration of 20 µmol/L, UMMS-4 produced a 17.53-fold reversal of MDR, but showed no effect on the sensitivity of drug-sensitive parental cells. UMMS-4, however, did not significantly alter the sensitivity of non-ABCB1 substrates in all cells and was unable to reverse ABCG2- and ABCC1-mediated MDR. Additionally, UMMS-4 profoundly inhibited the transport of rhodamine 123 (Rho 123) and doxorubicin (Dox) by the ABCB1 transporter. Furthermore, UMMS-4 did not alter the expression of ABCB1 at the mRNA and protein levels. In addition, the results of ATPase assays showed that UMMS-4 stimulated the ATPase activity of ABCB1. Taken together, we conclude that UMMS-4 antagonizes ABCB1-mediated MDR in cancer cells through direct inhibition of the drug efflux function of ABCB1. These findings may be useful for the development of safer and more effective MDR modulator.