Development of hydrophilic PES membranes using F127 and HKUST-1 based on the RTIPS method: Mitigate the permeability-selectivity trade-off.

In this study, to mitigate the permeability-selectivity trade-off effect, Pluronic F127 (F127) and HKUST-1 were employed to construct high-performance membranes based on the reverse thermally induced phase separation (RTIPS) method. F127, as a hydrophilic modifier, was applied to increase permeability and resist polyethersulfone (PES) membrane fouling, while the collapse of HKSUT-1 caused by its instability in pure water improved the permeability and selectivity of the membrane. Characterizations demonstrated the successful synthesis of HKUST-1, together with the successful introduction of HKSUT-1 and F127 in PES membranes. It was observed that the membrane prepared by the RTIPS process possessed a uniformly porous surface and sponge-like cross-section with excellent mechanical properties, higher permeability, and selectivity compared to the dense skin and finger-like cross-section of the membrane prepared by the nonsolvent induced phase separation (NIPS) method. Moreover, the permeation and bovine serum albumin (BSA) rejection rate of the optimal membrane reached 2378 L/m2 h and 89.3%, respectively, which were far higher than those of the pure membrane. Hydrophilic F127 and many microvoids formed by the collapse of HKUST-1, played an important role in excellent antifouling properties, high permeability, and selectivity by pure water flux (PWF), flux recovery rate (FRR), BSA flux, and COD removal rate tests. Overall, the membrane with F127 and HKSUT-1 prepared via the RTIPS method not only obtained excellent antifouling properties but also mitigated the permeability-selectivity trade-off.

Effect of OATP1B1 genetic polymorphism on the uptake of tamoxifen and its metabolite, endoxifen.

Overexpression lentivirus platform was established of OATP1B1 (organic anion transporting polypeptides 1B1) wild­type and mutant type genetic polymorphism in vitro, and using this platform we investigated and compared the uptake of tamoxifen and its metabolites by mutating the 388 and the 521 bases. The overexpression lentivirus cell platforms were successfully constructed, including OATP1B1*1a-HEK293T and OATP1B1*1b-HEK293T and OATP1B1*5-HEK293T cell model, the infection efficiency is not less than 80%. It shows a high level of gene expression at the mRNA and protein level. The tamoxifen and endoxifen can be taken up into the cells through organic anion transporter polypeptide 1B1, and OATP1B1521T>C inhibits the function of the transport protein, resulting in the content of drug in cell lysis liquid in OATP1B1*5-HEK293T group is lower than in OATP1B1*1a-HEK293T group (tamoxifen or endoxifen), with statistical significance. The content of the drug in cell lysis liquid in OATP1B1*1b-HEK293T group and the OATP1B1*1a-HEK293T group, similar with no statistical significance. These results suggest that tamoxifen and endoxifen can be transported by OATP1B1. However, OATP1B1 521T>C can inhibit the effects of OATP1B1 on tamoxifen and endoxifen in the cells.

Discovery of novel dual VEGFR2 and Src inhibitors using a multistep virtual screening approach.

AIM: Simultaneous inhibition of VEGFR2 and Src may enhance the efficacy of VEGFR2-targeted cancer therapeutics. Hence, development of dual inhibitors on VEGFR2 and Src can be a useful strategy for such treatments. MATERIALS & METHODS: A multistep virtual screening protocol, comprising ligand-based support vector machines method, drug-likeness rules filter and structure-based molecular docking, was developed and employed to identify dual inhibitors of VEGFR2 and Src from a large commercial chemical library. Kinase inhibitory assays and cell viability assays were then used for experimental validation. RESULTS: A set of compounds belonging to six different molecular scaffolds was identified and sent for biological evaluation. Compound 3c belonging to the 2-amino-3-cyanopyridine scaffold exhibited good antiproliferative effect and dual-target activities against VEGFR2 and Src. CONCLUSION: This study demonstrated the ability of the multistep virtual screening approach to identify novel multitarget agents.

New benzimidazole acridine derivative induces human colon cancer cell apoptosis in vitro via the ROS-JNK signaling pathway.

AIM: To investigate the mechanisms underlying anticancer action of the benzimidazole acridine derivative N-{(1H-benzo[d]imidazol-2-yl)methyl}-2-butylacridin-9-amine(8m) against human colon cancer cells in vitro. METHODS: Human colon cancer cell lines SW480 and HCT116 were incubated in the presence of 8m, and then the cell proliferation and apoptosis were measured. The expression of apoptotic/signaling genes and proteins was detected using RT-PCR and Western blotting. ROS generation and mitochondrial membrane depolarization were visualized with fluorescence microscopy. RESULTS: 8m dose-dependently suppressed the proliferation of SW480 and HCT116 cells with IC50 values of 6.77 and 3.33 µmol/L, respectively. 8m induced apoptosis of HCT116 cells, accompanied by down-regulation of Bcl-2, up-regulation of death receptor-5 (DR5), truncation of Bid, cleavage of PARP, and activation of caspases (including caspase-8 and caspase-9 as well as the downstream caspases-3 and caspase-7). Moreover, 8m selectively activated JNK and p38 without affecting ERK in HCT116 cells. Knockout of JNK1, but not p38, attenuated 8m-induced apoptosis. In addition, 8m induced ROS production and mitochondrial membrane depolarization in HCT116 cells. Pretreatment with the antioxidants N-acetyl cysteine or glutathione attenuated 8m-induced apoptosis and JNK activation in HCT116 cells. CONCLUSION: The new benzimidazole acridine derivative, 8m exerts anticancer activity against human colon cancer cells in vitro by inducing both intrinsic and extrinsic apoptosis pathways via the ROS-JNK1 pathway.

[Recurrence and surgical salvage of sinonasal squamous cell carcinoma].

OBJECTIVE: To analyze the significant clinicopathologic factors related to tumor recurrence in patients with sinonasal squamous cell carcinomas (SCC) and to evaluate the effectiveness and plausibility of surgical salvage in the recurrent cases. METHODS: The clinicopatholgic data of 107 patients with primary sinonasal SCC treated from 1996 to 2007 were analyzed retrospectively. Univariate and multivariate logistic regression analyses were used to define the risk factors related to tumor recurrence. Salvage surgery with was selectively carried out in the recurrent sinonasal SCC using different surgical approaches, including lateral rhinotomy midfacial degloving or combined craniofacial approach. Immediate reconstruction of major surgical defects were performed with latissimus dorsi flap, pectoralis major myocutanneous flap, temperalis fasciomuscular flap, free rectus abdominis flap and free radial forearm flap. All patients were routinely follwed up and 5-year survival were calculated using directly calculating method and Kaplan-Meier's method. RESULTS: The 5-year survival rate of 107 cases was 52.3% (56/107). Local recurrence was the most common pattern of tumor relapse. Forty-four of the 107 cases had recurrence. Logistic regression analysis showed the T stag was the most important impacting factor for tumor recurrence (OR = 0.258, P = 0.001). Of 44 cases with recurrence, 33 cases underwent salvage surgery and the 5-year survival rate after salvage surgery was 29.1%. CONCLUSIONS: T stag is the most important impacting factor for tumor recurrence. Salvage surgery with immediate reconstruction of major surgical defects should be carried out in the selective cases of recurrent sinonasal SCC.

[Clinical analysis of 71 cases of multiple primary cancers in head and neck squamous carcinomas].

OBJECTIVE: To study the location, treatment, life status of multiple primary cancers (MPCs) in head and neck squamous cell carcinomas. METHODS: The clinical data of 71 head and neck squamous carcinoma patients with MPCs were retrospectively analyzed. RESULTS: MPCs were seen in head and neck regions in 27 cases and in remote organs in 42 cases, two of which were triplicate primary cancers. Four cases were synchronous MPCs, including one patient with synchronous triplicate primary cancer. Other 67 cases were heterochronous MPCs, including one patient with heterochronous triplicate primary cancer. Of 67 heterochronous MPCs, the time interval between index tumor presentation and diagnosis of MPCs was eight months to twelve years. MPCs occurred in seventy percent index oral cavity squamous cancers, which were located in head and neck regions, and in sixty-two percent index hypopharynx cancers and seventy-nine percent index laryngeal cancers, which were located in remote organs. The incidence of MPCs in esophagus and lung was higher than that in other remote organs. Among the various MPCs in this serials, the incidence of the disease appeared to be the highest in esophagus, accounting for twenty-four percent of all cases. The total three- and five-year survival rates were 32.4% and 22.5%, respectively. Of all MPCs patients, the three-year survival rate for patients who received different therapies for their MPCs was obviously higher than that of untreated patients (P < 0.01, Chi-square test). CONCLUSIONS: Esophageal carcinoma is the most common second primary cancer among the various MPCs of the head and neck squamous carcinomas. Oral cavity cancers tend to have more MPCs in the head and neck regions, and laryngeal and hypopharyngeal cancers are easily to be associated with MPCs in the remote organs. Regular follow-up and early diagnosis with effective treatment can help to improve the survival of MPC patients in head and neck squamous cell carcinomas.

[Clinical pathology feature and prognostic factors of cervical lymph node metastases in hypopharyngeal carcinoma].

OBJECTIVE: To investigate the risk clinicopathological factors of primary tumor in the prediction of cervical lymph node metastases and the cervical lymph node prognostic factors in hypopharyngeal squamous cell carcinoma. METHODS: A retrospective study was carried out to review the histopathological data from 98 hypopharyngeal squamous cell carcinoma patients. The relationship between histopathological parameters and cervical lymph node metastases were evaluated by means of a univariate chi2 test and multivariate stepwise logistic regression model. And the Cox regression model was used to define possible pathological parameters of neck node affecting survival including N staging, presence of cervical lymph node metastases and extracapsular nodal spread, size and number of positive neck nodes, and levels of positive neck nodes. RESULTS: The overall 5-year survival rate of patients with hypopharyngeal carcinoma was 28.6%. In a univariate and multivariate analysis, it was confirmed that size and growth pattern of primary tumor correlated to cervical lymph node metastases. In a multivariate Cox regression analysis, the most significant prognostic factors of cervical lymph node were the size of positive neck nodes and level involved. CONCLUSIONS: Cervical lymph node metastases were one of the most significant prognostic factors of hypopharyngeal carcinoma. The identification of patients at risk for cervical lymph node metastases and the management of the neck by coping with pathological factors of cervical lymph node affecting survival are very important to improve the treatment and prognosis of hypopharyngeal carcinoma.