Metal-Organic Framework-Based Nanoagents for Effective Tumor Therapy by Dual Dynamics-Amplified Oxidative Stress.

Overproduction of reactive oxygen species (ROS) within tumors can cause oxidative stress on tumor cells to induce death, which has motivated us to develop ROS-mediated tumor therapies, such as typical photodynamic therapy (PDT) and Fenton reaction-mediated chemodynamic therapy (CDT). However, these therapeutic modalities suffer from compromised treatment efficacy owing to their limited generation of highly reactive ROS in a tumor microenvironment (TME). In this work, a nanoscale iron-based metal-organic framework, MIL-101(Fe), is synthesized as a Fenton nanocatalyst to perform the catalytic conversion of hydroxyl radicals (·OH) from hydrogen peroxide (H2O2) under the acidic environment and as a biocompatible and biodegradable nanocarrier to deliver a 5,10,15,20-tetrakis(4-carboxyphenyl)porphyrin (TCPP) photosensitizer for light-activated singlet oxygen (1O2) generation. By coupling such chemodynamic/photodynamic effects, the photosensitizer-integrated nanoagents (MIL-101(Fe)@TCPP) could enable more ROS production within tumors to induce amplified oxidative damage for tumor-specific synergistic therapy. In vitro results show that MIL-101(Fe)@TCPP nanoagents achieve the acid-responsive CDT and effective PDT, and synergistic CDT/PDT provides an enhanced therapeutic effect. Ultimately, based on such synergistic therapy, MIL-101(Fe)@TCPP nanoagents cause a significant tumor growth inhibition in vivo without severe side effects, showing great potential for anti-tumor application.

UBE2C Is a Potential Biomarker of Intestinal-Type Gastric Cancer With Chromosomal Instability.

This study explored potential biomarkers associated with Lauren classification of gastric cancer. We screened microarray datasets on gastric cancer with information of Lauren classification in gene expression omnibus (GEO) database, and compared differentially expressing genes between intestinal-type or diffuse-type gastric cancer. Four sets of microarray data (GSE2669, GSE2680, GDS3438, and GDS4007) were enrolled into analysis. By differential gene analysis, UBE2C, CDH1, CENPF, ERO1L, SCD, SOX9, CKS1B, SPP1, MMP11, and ANLN were identified as the top genes related to intestinal-type gastric cancer, and MGP, FXYD1, FAT4, SIPA1L2, MUC5AC, MMP15, RAB23, FBLN1, ANXA10, and ADH1B were genes related to diffuse-type gastric cancer. We comprehensively validated the biological functions of the intestinal-type gastric cancer related gene UBE2C and evaluated its clinical significance on 1,868 cases of gastric cancer tissues from multiple medical centers of Shanghai, China. The gain of copy number on 20q was found in 4 out of 5 intestinal-type cancer cell lines, and no similar copy number variation (CNV) was found in any diffuse-type cancer cell line. Interfering UBE2C expression inhibited cell proliferation, migration and invasion in vitro, and tumorigenesis in vivo. Knockdown of UBE2C resulted in G2/M blockage in intestinal-type gastric cancer cells. Overexpression of UBE2C activated ERK signal pathway and promoted cancer cell proliferation. U0126, an inhibitor of ERK signaling pathway reversed the oncogenic phenotypes caused by UBE2C. Moreover, overexpression of UBE2C was identified in human intestinal-type gastric cancer. Overexpression of UBE2C protein predicted poor clinical outcome. Taken together, we characterized a group of Lauren classification-associated biomarkers, and clarified biological functions of UBE2C, an intestinal-type gastric cancer associated gene. Overexpression of UBE2C resulted in chromosomal instability that disturbed cell cycle and led to poor prognosis of intestinal-type gastric cancer.

Targeting mTORC2 component rictor inhibits cell proliferation and promotes apoptosis in gastric cancer.

The mammalian target of rapamycin (mTOR) kinase acts downstream of phosphoinositide 3-kinase/Akt and plays an important role in tumor growth and progression of gastric cancer. It is well characterized that mTOR complex1 (mTORC1) controls cell metabolism and proliferation, whereas the contribution of mTOR complex2 (mTORC2) and its key component, Rictor, remains poorly understood. Therefore, we investigated clinical significance of Rictor expression by immunohistochemical analysis of 391 tissue samples from gastric cancer patients. In addition, the roles of Rictor in cell proliferation, apoptosis, migration and invasion in vitro were evaluated by RNA interference. The results showed that over expression of Rictor was associated with increased tumor size, depth of tumor invasion, lymph node metastasis and advanced TNM stage, together with poorer overall and relapse-free survival. Stable sh-RNA mediated down-regulation of Rictor significantly inhibited SGC7901 and MGC803 gastric cancer cells proliferation, migration and invasion. Furthermore, Rictor knockdown attenuated cell cycle progression and enhanced apoptosis, synergistic with treatment of mTORC1 inhibitor rapamycin owing to abrogating the feedback activation of Akt. Our findings identify Rictor as an important mediator of tumor progression and metastasis, providing the rationale for targeting both mTORC1 and mTORC2 as part of therapeutic strategy for gastric cancer.

Investigation of the bioequivalence of two lansoprazole formulations in healthy Chinese volunteers after a single oral administration.

The objective of this study was to compare two lansoprazole products (the reference brand enteric-coated capsules and the test generic enteric-coated tablets), and the key pharmacokinetic (PK) parameters for both formulations and their metabolites were assessed. The study used an open-label, randomized two-period crossover design with an 8-day washout period between doses in 24 healthy subjects under fasting conditions. The concentration of lansoprazole and its two metabolites was determined using liquid chromatography-tandem mass spectrometry (LC-MS/MS) method. The in vitro release of lansoprazole from the test and reference formulations was within the acceptable limits. The relationship between concentration and peak area ratio was found to be linear within the range for lansoprazole and metabolites. The point estimates (ratios of geometric mean) of lansoprazole and two main metabolites were between 94.3% and 105.1% for AUC0-t, AUC0-∞, and Cmax. No statistically significant difference between the two formulations was found. The results of in vitro and in vivo suggested equivalent clinical efficacy of the two brands.

MicroRNA-187 inhibits tumor growth and invasion by directly targeting CD276 in colorectal cancer.

Aberrantly expressed microRNAs contribute to the initiation and progression of human cancers. However, the underlying functions of microRNA-187 (miR-187) in colorectal cancer (CRC) remain largely unexplored. Here, we demonstrated that miR-187 was significantly down-regulated in CRC tissues and cell lines compared to their normal counterparts. By Kaplan-Meier analysis, we revealed that decreased miR-187 expression was closely associated with shorter overall survival and relapse-free survival of patients with CRC. By gain- and loss-of-function studies, we showed that miR-187 remarkably suppressed CRC cell proliferation, migration, invasion, and promoted cell apoptosis. Furthermore, bioinformatics analysis and luciferase reporter assay identified that CD276 was the direct functional target of miR-187 in CRC. Genetic silencing of CD276 recapitulated similar phenotype as observed in over-expression of miR-187, and restoration of CD276 completely rescued the inhibitory effect of miR-187 in CRC cells. Taken together, our study implied the essential roles of miR-187 in suppressing CRC progression, and a novel link between miR-187 and CD276 in CRC.

Elevated Rictor expression is associated with tumor progression and poor prognosis in patients with gastric cancer.

The rapamycin insensitive companion of mTOR (Rictor) is an essential subunit of mTOR complex 2 (mTORC2), maintains the integrity of the complex and functions as regulator of Akt full activation. Rictor has been implicated to be involved in growth and progression of malignancies, however, little is known about its expression and prognostic role in gastric cancer in particular. Therefore, we investigated the relationship of Rictor expression with clinical outcomes, together with pAktSer473 and pS6, two downstream substrates of mTORC2 and mTORC1, in 396 gastric cancer tissue samples via immunohistochemistry. The results showed that 74.0% and 55.8% of tumors were Rictor and pAktSer473 positive staining, respectively, which correlated well with each other. Patients with positive expressions had poorer overall survival and relapse-free survival compared with those negative staining. Both Rictor and pAktSer473 expression were associated with lymph node metastasis, TNM stage, and WHO grading. Rictor was also correlated with tumor size, depth of invasion, and tumor thrombus, while pAktSer473 was also correlated with distant metastasis. In spite of 67.4% expression rate was presented in gastric cancer tissues, no significant association was observed between pS6Ser235/236, representing mTORC1 activity, and clinicopathological features or prognosis. These results suggest that mTORC2/Rictor/pAkt may play a more important role than mTORC1/pS6 in tumor progression, which could act as a prognostic biomarker or potential therapeutic target in gastric cancer.

[Further recognition and improvement of multimodality treatment for advanced gastric cancer].

Gastric cancer is one of the most common malignancies in China, which remains in high incidence and mortality. At present, radical surgery remains the cornerstone of multidisciplinary treatment in advanced gastric cancer, but is not the only one. In order to improve prognosis, it is necessary for surgeons to realize and emphasize the idea of comprehensive treatment. Accurate preoperative TNM staging is a prerequisite for selecting reasonable therapeutic modality. Based on standard surgery, multimodal treatments involving (neo-) adjuvant chemotherapy, radiotherapy or molecular target agents still need to be optimized for the best oncologic outcome with minimal morbidities. As to metastatic and late cases, personalized strategy is being acknowledged to prolong survival time and improve quality of life. A deeper understanding of high heterogeneity and biological characteristics of gastric cancer should be carried out, and multidisciplinary team collaboration is quite important to achieve an optimal treatment mode both standardized and individualized, which will benefit every patient.

Rictor is an independent prognostic factor for endometrial carcinoma.

Early-stage endometrial carcinoma (EC) patients have a high cure rate; however, those with high-risk factors may have poor prognosis. Thus, there is an urgent need for searching for new prognostic molecules to more accurately predict survival of patients. We detected the Rictor mRNA expression level in 30 fresh EC tissue and 17 normal endometrial tissue samples with real-time quantitative RT-PCR and Rictor protein expression level in 134 (test cohort) and 115 (validation cohort) paraffin tissue samples by immunohistochemistry, analyzed the correlation between variables and overall survival (OS) using Cox proportional hazards regression, compared the prognostic accuracy of Rictor with other clinicopathological risk factors by logistic regression. The results showed that Rictor mRNA expression of EC is higher than that of normal endometrium; Rictor protein expression level was closely correlated with FIGO stage, grade and vascular invasion in both cohorts; a univariate analysis showed that the pathological type, stage, grade, vascular invasion, lymphatic metastasis and Rictor were predictors of OS in both cohorts; furthermore, multivariate Cox proportional hazards regression analysis indicated that vascular invasion and Rictor were independent prognostic factors for EC in both cohorts; an ROX curve comparison showed that the area under the curve (AUC) for Rictor combined with other clinicopathological prognostic factors was higher than any individual factor or other clinicopathological prognostic factors' combination. Based on the above data, we concluded that Rictor is an independent prognostic factor for EC. It combined with other clinicopathological risk factors was a stronger prognostic model than individual risk factor or their combination.

Prognostic assessment of different metastatic lymph node staging methods for gastric cancer after D2 resection.

AIM: To compare the prognostic assessment of lymph node ratio and absolute number based staging system for gastric cancer after D2 resection. METHODS: The clinical, pathologic, and long-term follow-up data of 427 patients with gastric cancer that underwent D2 curative gastrectomy were retrospectively analyzed. The relationships between the metastatic lymph node ratio (MLR), log odds of positive lymph nodes (LODDS), and positive lymph nodes (pN) staging methods and the long-term prognoses of the patients were compared. In addition, the survival curves, accuracy, and homogeneity were compared with stratification to evaluate the prognostic assessment of the 3 methods when the number of tested lymph nodes was insufficient (< 10 and 10-15). RESULTS: MLR [hazard ratio (HR) = 1.401, P = 0.012], LODDS (HR = 1.012, P = 0.034), and pN (HR = 1.376, P = 0.005) were independent risk factors for gastric cancer patients. The receiver operating characteristic (ROC) curves showed that the prognostic accuracy of the 3 methods was comparable (P > 0.05). Spearman correlation analysis confirmed that MLR, LODDS, and pN were all positively correlated with the total number of tested lymph nodes. When the number of tested lymph node was < 10, the value of survival curves staged by MLR and LODDS was superior to those of pN staging. However, the difference in survival curves between adjacent stages was not significant. In addition, the survival rate of stage 4 patients using the MLR and LODDS staging methods was 26.7% and 27.3% with < 10 lymph node, respectively which were significantly higher than the survival rate of patients with > 15 tested lymph nodes (< 4%). The ROC curve showed that the accuracy of the prognostic assessment of MLR, LODDS, and pN staging methods was comparable (P > 0.05), and the area under the ROC curve of all 3 methods were increased progressively with the enhanced levels of examined lymph nodes. In addition, the homogeneity of the 3 methods in patients with ≤ 15 tested lymph nodes also showed no significant difference. CONCLUSION: Neither MLR or LODDS could reduce the staging bias. A sufficient number of tested lymph nodes is key to ensure an accurate prognosis for patients underwent D2 radical gastrectomy.