Enhancing Photoelectrochemical Water Oxidation on WO3 via Electrochromic Modulation: Universal Effects and Mechanistic Insights.

Although WO3 exhibits both electrochromic and photoelectrochemical (PEC) properties, there is no research conducted to investigate the correlation between them. The study herein reports the electrochromic enhancement of PEC activity on WO3. The electrochromic WO3 (e-WO3) exhibits a significantly enhanced activity for PEC water oxidation compared to raw WO3 (r-WO3), with a limiting photocurrent density three times that of r-WO3. The electrochromic enhancement of PEC activity is universal and independent of the type of cations inserted during electrochromism. Decoloring reduces the PEC activity but a simple re-coloring restores the activity to its maximum value. Electrochromism induces large amounts of oxygen vacancies and surface states, the former improving the electron density of WO3 and the latter facilitating the hole transfer across e-WO3/electrolyte interface. It is proved that the electrochromic enhancement effect is due to the significantly improved electron-hole separation efficiency and the charge transfer efficiency across the WO3/electrolyte interface.

Local tuning of radiomics-based model for predicting pathological response to neoadjuvant chemoradiotherapy in locally advanced rectal cancer.

PURPOSE: This study aims to further enhance a validated radiomics-based model for predicting pathologic complete response (pCR) after chemo­radiotherapy in locally advanced rectal cancer (LARC) for use in clinical practice. METHODS: A generalized linear model (GLM) to predict pCR in LARC patients previously trained in Europe and validated with an external inter-continental cohort (59 patients), was first examined with further 88 intercontinental patient datasets to assess its reproducibility; then new radiomics and clinical features, and validation methods were investigated to build a new model for enhancing the pCR prediction for patients admitted to our department. The patients were divided into training group (75%) and validation group (25%) according to their demographic. The least absolute shrinkage and selection operator (LASSO) logistic regression was used to reduce the dimensionality of the extracted features of the training group and select the optimal ones; the performance of the reference GLM and enhanced models was compared through the area under curve (AUC) of the receiver operating characteristics. RESULTS: The value of AUC of the reference model was 0.831 (95% CI, 0.701-0.961), and 0.828 (95% CI, 0.700-0.956) in the original and new validation cohorts, respectively, showing a reproducibility in the applicability of the GLM model. Eight features were found to be significant with LASSO and used to establish an enhanced model. The AUC of the enhanced model of 0.926 (95% CI, 0.859-0.993) for training, and 0.926 (95% CI, 0.767-1.00) for the validation group shows better performance than the reference model. CONCLUSIONS: The GLM model shows good reproducibility in predicting pCR in LARC; the enhanced model has the potential to improve prediction accuracy and may be a candidate in clinical practice.

Identification of prognostic values defined by copy number variation, mRNA and protein expression of LANCL2 and EGFR in glioblastoma patients.

BACKGROUND: Epidermal growth factor receptor (EGFR) and lanthionine synthetase C-like 2 (LanCL2) genes locate in the same amplicon, and co-amplification of EGFR and LANCL2 is frequent in glioblastoma. However, the prognostic value of LANCL2 and EGFR co-amplification, and their mRNA and protein expression in glioblastoma remain unclear yet. METHODS: This study analyzed the prognostic values of the copy number variations (CNVs), mRNA and protein expression of LANCL2 and EGFR in 575 glioblastoma patients in TCGA database and 100 glioblastoma patients in tumor banks of the Shenzhen Second People's Hospital and the Sun Yat-sen University Cancer Center. RESULTS: The amplification of LANCL2 or EGFR, and their co-amplification were frequent in glioblastoma of TCGA database and our tumor banks. A significant correlation was found between the CNVs of LANCL2 and EGFR (p < 0.001). CNVs of LANCL2 or EGFR were significantly correlated with IDH1/2 mutation but not MGMT promoter methylation. Multivariate analysis showed that LANCL2 amplification was significantly correlated with reduced overall survival (OS) in younger (< 60 years) glioblastoma patients of TCGA database (p = 0.043, HR = 1.657) and our tumor banks (p = 0.018, HR = 2.199). However, LANCL2 or EGFR amplification, and their co-amplification had no significant impact on OS in older (≥ 60 years) or IDH1/2-wild-type glioblastoma patients. mRNA and protein overexpression of LANCL2 and EGFR was also frequently found in glioblastoma. The mRNA expression rather than the protein expression of LANCL2 and EGFR was positively correlated (p < 0.001). However, mRNA or protein expression of EGFR and LANCL2 was not significantly correlated with OS of glioblastoma patients. The protein expression level of LANCL2, rather than EGFR, was elevated in relapsing glioblastoma, compared with newly diagnosed glioblastoma. In addition, the intracellular localization of LanCL2, not EGFR, was associated with the grade of gliomas. CONCLUSIONS: Taken together, amplification and mRNA overexpression of LANCL2 and EGFR, and their co-amplification and co-expression were frequent in glioblastoma patients. Our findings suggest that amplification of LANCL2 and EGFR were the independent diagnostic biomarkers for glioblastoma patients, and LANCL2 amplification was a significant prognostic factor for OS in younger glioblastoma patients.

Synergism between the phosphatidylinositol 3-kinase p110ß isoform inhibitor AZD6482 and the mixed lineage kinase 3 inhibitor URMC-099 on the blockade of glioblastoma cell motility and focal adhesion formation.

BACKGROUND: Glioblastoma multiforme, the most aggressive and malignant primary brain tumor, is characterized by rapid growth and extensive infiltration to neighboring normal brain parenchyma. Our previous studies delineated a crosstalk between PI3K/Akt and JNK signaling pathways, and a moderate anti-glioblastoma synergism caused by the combined inhibition of PI3K p110ß (PI3Kß) isoform and JNK. However, this combination strategy is not potent enough. MLK3, an upstream regulator of ERK and JNK, may replace JNK to exert stronger synergism with PI3Kß. METHODS: To develop a new combination strategy with stronger synergism, the expression pattern and roles of MLK3 in glioblastoma patient's specimens and cell lines were firstly investigated. Then glioblastoma cells and xenografts in nude mice were treated with the PI3Kß inhibitor AZD6482 and the MLK3 inhibitor URMC-099 alone or in combination to evaluate their combination effects on tumor cell growth and motility. The combination effects on cytoskeletal structures such as lamellipodia and focal adhesions were also evaluated. RESULTS: MLK3 protein was overexpressed in both newly diagnosed and relapsing glioblastoma patients' specimens. Silencing of MLK3 using siRNA duplexes significantly suppressed migration and invasion, but promoted attachment of glioblastoma cells. Combined inhibition of PI3Kß and MLK3 exhibited synergistic inhibitory effects on glioblastoma cell proliferation, migration and invasion, as well as the formation of lamellipodia and focal adhesions. Furthermore, combination of AZD6482 and URMC-099 effectively decreased glioblastoma xenograft growth in nude mice. Glioblastoma cells treated with this drug combination showed reduced phosphorylation of Akt and ERK, and decreased protein expression of ROCK2 and Zyxin. CONCLUSION: Taken together, combination of AZD6482 and URMC-099 showed strong synergistic anti-tumor effects on glioblastoma in vitro and in vivo. Our findings suggest that combined inhibition of PI3Kß and MLK3 may serve as an attractive therapeutic approach for glioblastoma multiforme.

Design, synthesis and biological evaluation of novel indole-based oxalamide and aminoacetamide derivatives as tubulin polymerization inhibitors.

A series of novel indole-based oxalamide and aminoacetamide derivatives were designed, synthesized, and evaluated for antiproliferative activities. Preliminary results revealed that compound 8g exhibited significant antiproliferative effect against PC-3, HeLa and HCT-116 cell lines. Flow cytometric analysis of the cell cycle demonstrated the compound 8g induced the cell cycle arrest at G2/M phase in HeLa cell lines. Immunocytochemistry revealed loss of intact microtubule structure in cells treated with 8g andinhibition of tubulinpolymerization. Additionally, molecular docking analysis suggested that 8g formed stable interactions in the colchicine-binding site of tubulin. These preliminary results demonstrated that a new class of novel indole-based oxalamide and aminoacetamide derivatives described in the investigation could be developed as potential scaffolds to new anticancer agents.

Discovery and optimization of 3,4,5-trimethoxyphenyl substituted triazolylthioacetamides as potent tubulin polymerization inhibitors.

Based on our previous research, three series of new triazolylthioacetamides possessing 3,4,5-trimethoxyphenyl moiety were synthesized, and evaluated for antiproliferative activities and inhibition of tubulin polymerization. The most promising compounds 8b and 8j demonstrated more significant antiproliferative activities against MCF-7, HeLa, and HT-29 cell lines than our lead compound 6. Moreover, analogues 8f, 8j, and 8o manifested more potent antiproliferative activities against HeLa cell line with IC50 values of 0.04, 0.05 and 0.16 µM, respectively, representing 100-, 82-, and 25-fold improvements of the activity compared to compound 6. Furthermore, the representative compound, 8j, was found to induce significant cell cycle arrest at the G2/M phase in HeLa cell lines via a concentration-dependent manner. Meanwhile, compound 8b exhibited the most potent tubulin polymerization inhibitory activity with an IC50 value of 5.9 µM, which was almost as active as that of CA-4 (IC50 = 4.2 µM). Additionally, molecular docking analysis suggested that 8b formed stable interactions in the colchicine-binding site of tubulin.

Facile one-pot synthesis, antiproliferative evaluation and structure-activity relationships of 3-amino-1H-indoles and 3-amino-1H-7-azaindoles.

A highly efficient method has been developed for the one-pot synthesis of substituted 3-amino-1H-indole and 3-amino-1H-7-azaindole derivatives starting from ethyl 2-cyanophenylcarbamate/ethyl 3-cyanopyridin-2-ylcarbamate, and α-bromoketones in good to excellent yields. All newly synthesized analogues were screened for their antiproliferative activities against four cancer cell lines. The most promising compound 8v demonstrated 13-, 5-, and 1.4-fold improvement compared to fluorouracil in inhibiting HeLa, HepG2, and MCF-7 cell proliferation with IC50 values of 3.7, 8.0, and 19.9 µM, respectively. Furthermore, 8v induced significant cell cycle arrest at the G2/M phase in HeLa cell lines via a concentration-dependent manner. These encouraging findings indicate that the common 3-amino-1H-7-azaindole is a very favorable scaffold for the design of novel anticancer small-molecule drugs.

Novel [1,2,4]triazolo[1,5-a]pyrimidine derivatives as potent antitubulin agents: Design, multicomponent synthesis and antiproliferative activities.

As restricted CA-4 analogues, a novel series of [1,2,4]triazolo[1,5-a]pyrimidines possessing 3,4,5-trimethoxylphenyl groups has been achieved successfully via an efficient one-pot three-component reaction of 3-(3,4,5-trimethoxyphenyl)-1H-1,2,4-triazol-5-amine, 1,3-dicarbonyl compounds and aldehydes. Initial biological evaluation demonstrated some of target compounds displayed potent antitumor activity in vitro against three cancer cell lines. Among them, the most highly active analogue 26 inhibited the growth of HeLa, and A549 cell lines with IC50 values at 0.75, and 1.02 µM, respectively, indicating excellent selectivity over non-tumoural cell line HEK-293 (IC50 = 29.94 µM) which suggested that the target compounds might possess a high safety index. Moreover, cell cycle analysis illustrated that the analogue 26 significantly induced HeLa cells arrest in G2/M phase, meanwhile the compound could dramatically affect cell morphology and microtubule networks. In addition, compound 28 exhibited potent anti-tubulin activity with IC50 values of 9.90 µM, and molecular docking studies revealed the analogue occupied the colchicine-binding site of tubulin. These observations suggest that [1,2,4]triazolo[1,5-a]pyrimidines represent a new class of tubulin polymerization inhibitors and well worth further investigation aiming to generate potential anticancer agents.

Comparison of Eversion Carotid Endarterectomy and Patch Carotid Endarterectomy: A Retrospective Study of 6 Years of Experience.

BACKGROUND The aim of this study was to compare early and long-term results of eversion carotid endarterectomy (e-CEA) and patch carotid endarterectomy (p-CEA). MATERIAL AND METHODS In a retrospective study, we collected data on 441 patients who underwent CEA (e-CEA=211 vs. p-CEA=230) between October 2009 and October 2015 at our institute. Economic costs, postoperative hospital days, use of shunts and antibiotics, early (30-day) complications, long-term restenosis, and mortality rates were compared between groups during 4 to 76 months of follow-up. RESULTS Patients in the p-CEA group had a significantly higher percentage of antibiotic use (58.3% vs. 27%, respectively; P0.05). Long-term complication, including stroke or heart attack, recurrent stenosis rate, and mortality rate, showed no difference between the 2 groups (all P>0.05). Kaplan-Meier analysis shows that the recurrent stenosis-free and survival rates were not significantly different between the 2 groups (P=0.867, P=0.177, respectively). CONCLUSIONS The adverse event rates of perioperative and long-term follow-up showed no significant difference between the e-CEA and p-CEA groups. Both e-CEA and p-CEA are effective for carotid artery stenosis.