[Chemical profiling from water extract of Wikstroemia indica by UPLC-Q-TOF-MS/MS].

In this study,a method using ultra performance liquid chromatography tandem quadrupole time-of-flight mass spectrometry( UPLC-Q-TOF-MS/MS) was established to identify complicated chemical constituents of Wikstroemia indica. Chromatographic separation was performed on an AcclaimTMRSLC 120-C18 column( 2. 1 mm×100 mm,2. 2 µm) using gradient elution with 0. 2% ammonium formate buffer salt solution( A)-0. 2% ammonium formate buffer salt solution methanol( B) as mobile phase. The column temperature was maintained at 30 ℃. The analytes were determined by positive and negative ion modes with electro-spray ionization source. A total of 52 compounds( including eleven coumarins,thirteen flavonoids,ten lignans,two amides,four phenolic acids,six sesquiterpenes and six other compounds) were identified or tentatively characterized from the water extract of W. indica by comparing their retention times and MS spectra with those of authentic standards or literature datas. Three compounds were found for the first time from W.indica namely isomer of indicanone,ß-hydroxypropiovanillone and epiprocurcumenol. Furthermore,the fragmentation rules of some compounds were speculated and summarized. In addition,the cleavage pathways of guaiane sesquiterpenes were described for the first time,which can provide reference for studying the fragmentation pathways of similar compounds. This study provides an easy way to identify chemical constituents of traditional Chinese medicine and a basis for the further study on chemical fundamentals of W. indica.

[Mechanism research of curcumin on cancer cells based on cell metabolic profiling].

In this study, gas chromatography coupled with mass spectrometry(GC-MS) was used to analyze the changes of 12 kinds of cancer cells treated by curcumin. The related differential metabolites were screened and the metabolic pathways were analyzed to explore the anti-tumor mechanism of curcumin. Methyl thiazol tetrazolium(MTT) assay was used to detect the 50% inhibiting concentration(IC_(50)) of curcumin on 12 human tumor cells. After treatment with curcumin for 48 h, the cells were collected and analyzed by GC-MS, followed by pathway analysis and multivariate data analysis including principal component analysis(PCA), orthogonal partial least squares discriminant analysis(OPLS-DA) and One-way analysis of variance(ANOVA),etc. Overall, 34 metabolites showed significant concentration changes after intervention for 48 h, mainly involving multiple metabolic pathways, including lysine degradation, glycine, serine and threonine metabolism, arginine and proline metabolism, cysteine and methionine metabolism, aminoacyl-tRNA biosynthesis, primary bile acid biosynthesis, lysine biosynthesis. In this study, the anti-tumor mechanisms of curcumin interfering with energy metabolism, amino acid metabolism, microtubule system, protein synthesis and oxidative stress response of tumor cells were analyzed from the perspective of metabolism, providing a new reference for further tumor pharmacology study.

Frequency of the acquired resistant mutation T790 M in non-small cell lung cancer patients with active exon 19Del and exon 21 L858R: a systematic review and meta-analysis.

BACKGROUND: Although EGFR-TKI is the preferred treatment for NSCLC patients with sensitive mutations, subsequent drug resistance is almost inevitable. The specific mechanisms of EGFR-TKI drug resistance can be identified through repeat biopsy. METHODS: To better understand the clinical characteristics of TKI resistance in NSCLC patients, we retrospectively reviewed studies of acquired TKI drug resistance using repeat biopsy from the last decade. The relevant literature was retrieved from January 2005 to August 2015 in the databases Medline and Embase. The search terms were NSCLC or non-small cell lung cancer and T790 M. RESULTS: A total of 478 patients with NSCLC tested by repeated biopsy were confirmed to have acquired TKI resistance. Analysis indicated that 240 patients (50.21%) of the 478 patients with acquired TKI drug resistance had the T790 M mutation. The detection rate of T790 M in different repeat biopsy sites was also different, with the highest positive rate in the lymph nodes (60%) and the lowest detection rate in cerebrospinal fluid (less than 5%). In addition, patients with T790 M had longer overall survival compared to those without the mutation (P < 0.05). Of the 240 patients with T790 M mutations, 213 patients showed results consistent with the mutation analysis before TKI treatment, and the rate of patients with the L858R point mutation along with the T790 M mutation was lower than that of patients with the exon 19 deletion (36.42% to 58.30%). CONCLUSIONS: T790 M occurred more frequently in patients with the exon 19 deletion than in those with exon 21 L858R, which gave the survival benefit of the T790 M mutation and may explain why patients with the exon 19 deletion had an improved overall survival.

Rapidly recoverable, anti-fatigue, super-tough double-network hydrogels reinforced by macromolecular microspheres.

In this study, a novel strategy was designed to prepare rapidly recoverable, anti-fatigue, super-tough double-network hydrogels by introducing macromolecular microspheres (MMs) as cross-linking centers for hydrophobic associations. MMs were prepared via emulsion polymerization using butyl acrylate (BA) as a main component and dicyclopentyl acrylate (DCPA) as a cross-linker. Then, a double-network (DN) hydrogel was prepared using gelatin as the first network and a copolymer of acrylamide and hexadecyl methacrylate stabilized by MMs as the second network. As a result, the DN hydrogels that were toughened by MMs exhibited an excellent fracture strength of 1.48 MPa and a fracture strain of 2100%. Moreover, the hydrogels exhibited rapid recoverability and fatigue resistance. Therefore, the strategy would open up a novel avenue for the toughening of DN hydrogels for biomedical applications.

Effect of nicotine dependence on quality of life and sleep quality in patients with lung cancer who continue to smoke after diagnosis.

BACKGROUND: Hundreds of millions of Chinese individuals continue to smoke and rates of lung cancer still continue to rise. However, there were few studies that examined the effects of nicotine dependence on quality of life (QOL) and sleep quality in lung cancer patients. This study aimed to investigate the effect of nicotine dependence on QOL and sleep quality in lung cancer patients who continue to smoke after diagnosis. METHODS: This cross-sectional survey study included 202 patients with lung cancer. Smokers were separated into two groups based on the Fagerstrom Test for Nicotine dependence: the low dependence (LD) (<4 score) group (n=59) and the high dependence (HD) (≥4 score) group (n=143). Both Chinese version of the European Organization for Research and Treatment of Cancer Quality of Life Core Questionnaire 30 (EORTC QLQ-C30) and Chinese version of Pittsburgh Sleep Quality Index (PSQI) were used to evaluate the two groups of lung cancer patients. Then we analyzed the difference of QOL and sleep quality between two distinct nicotine dependence groups. RESULTS: Physical functioning, role functioning, emotional functioning, cognitive functioning, global health status and social functioning items in the LD group were significantly higher than the HD group (P<0.001). Fatigue, nausea/vomiting, pain, dyspnea, insomnia, appetite loss, diarrhea and financial problems in the LD group were significantly lower than those in the HD group (P<0.001). Significantly higher scores in the HD group were found concerning the three sleep components including sleep duration, sleep efficiency and daytime function. The mean global PSQI score in the HD group was significantly higher than the LD group (P=0.014). CONCLUSIONS: These findings suggest that lung cancer patients who continue to smoke after diagnosis should receive health education in order to improve their QOL and quality of sleep after the word education. This can be useful for clinicians and nurses who are trying to motivate smokers to quit smoking.

Robust, tough and anti-fatigue cationic latex composite hydrogels based on dual physically cross-linked networks.

Dual physically cross-linked hydrogels, which are triggered by cationic latexes as hydrophobic association and ionic crosslinking centers, were easily fabricated via a one-pot in situ polymerization method. First, the hydrophobic alkyl chains of hydrophobic monomers are adsorbed on the surface of latex microspheres and stabilized in the presence of surfactants, forming hydrophobic association centers as the first physical crosslinking points. Meanwhile, the anionic sulfate radicals dissociated by persulphate are attracted towards the cationic molecular chains of latex microspheres through ionic interactions, forming the secondary physical crosslinking centers, and initiate the copolymerization between acrylamide and hydrophobic vinyl monomers. The fabricated hydrogel exhibited high tensile strength of 1.32MPa, a remarkable toughness of 4.53MJm-3, excellent self-recovery properties and fatigue resistance. Therefore, the current work provides a promising strategy for designing novel hydrogels via multiple physical interactions and devoid of any chemical crosslinking. The novel design of hydrogels can enhance their mechanical properties and expand their biomedical applications.

pH-Triggered Charge-Reversal Polyurethane Micelles for Controlled Release of Doxorubicin.

A series of pH-triggered charge-reversal polyurethane copolymers (PS-PUs) containing methoxyl-poly(ethylene glycol) (mPEG), carboxylic acid groups, and piperazine groups is presented in this work. The obtained PS-PUs copolymers can form into stable micelles at pH 7.4, which response to a narrow pH change (5.5-7.5) and show a tunable pH-triggered charge-reversal property. Doxorubicin (DOX) is encapsulated into the PS-PU micelles as a model drug. The drug release of DOX-loaded PS-PU micelles shows an obviously stepped-up with reducing the pH. Meanwhile, it is found that the charge-reversal property can improve the cellular uptake behavior and intracellular drug release in both HeLa cells and MCF-7 cells. Additionally, the time-dependent cytotoxicity of the DOX-loaded PS-PU micelles is confirmed by MTT assay. Attributed to the tunable charge-reversal property through changing the molar ratio of piperazine/carboxyl, the PS-PU micelles will be a potential candidate as an intelligent drug delivery system in future studies.

pH-Responsive biodegradable polymeric micelles with anchors to interface magnetic nanoparticles for MR imaging in detection of cerebral ischemic area.

A novel type of pH-responsive biodegradable copolymer was developed based on methyloxy-poly(ethylene glycol)-block-poly[dopamine-2-(dibutylamino) ethylamine-l-glutamate] (mPEG-b-P(DPA-DE)LG) and applied to act as an intelligent nanocarrier system for magnetic resonance imaging (MRI). The mPEG-b-P(DPA-DE)LG copolymer was synthesized by a typical ring opening polymerization of N-carboxyanhydrides (NCAs-ROP) using mPEG-NH2 as a macroinitiator, and two types of amine-terminated dopamine groups and pH-sensitive ligands were grafted onto a side chain by a sequential aminolysis reaction. This design greatly benefits from the addition of the dopamine groups to facilitate self-assembly, as these groups can act as high-affinity anchors for iron oxide nanoparticles, thereby increasing long-term stability at physiological pH. The mPEG moiety in the copolymers helped the nanoparticles to remain well-dispersed in an aqueous solution, and pH-responsive groups could control the release of hydrophobic Fe3O4 nanoparticles in an acidic environment. The particle size of the Fe3O4-loaded mPEG-b-P(DPA-DE)LG micelles was measured by dynamic light scattering (DLS) and cryo-TEM. The superparamagnetic properties of the Fe3O4-loaded mPEG-b-P(DPA-DE)LG micelles were confirmed by a superconducting quantum interference device (SQUID). T2-weighted magnetic resonance imaging (MRI) of Fe3O4-loaded mPEG-b-P(DPA-DE)LG phantoms exhibited enhanced negative contrast with an r2 relaxivity of approximately 106.7 mM(-1) s(-1). To assess the ability of the Fe3O4-loaded mPEG-P(DE-DPA)LG micelles to act as MRI probes, we utilized a cerebral ischemia disease rat model with acidic tissue. We found that a gradual change in contrast in the cerebral ischemic area could be visualized by MRI after 1 h, and maximal signal loss was detected after 24 h post-injection. These results demonstrated that the Fe3O4-loaded mPEG-b-P(DPA-DE)LG micelles can act as pH-triggered MRI probes for diagnostic imaging of acidic pathological tissues.

Efficacy of first-line chemotherapy affects the second-line setting response in patients with advanced non-small cell lung cancer.

BACKGROUND: Chemotherapy is the mainstay of treatment for the majority of patients with advanced non- small cell lung cancer (NSCLC) without driver mutations and many receive therapies beyond first-line. Second- line chemotherapy has been disappointing both in terms of response rate and survival and we know relatively little about the prognostic factors. MATERIALS AND METHODS: One thousand and eight patients with advanced NSCLC who received second-line chemotherapy after progression were reviewed in Shanghai Pulmonary Hospital, China, from September 2005 to July 2010. We analyzed the effects of potential prognostic factors on the outcomes of second-line chemotherapy (overall response rate, ORR; progression free survival, PFS; overall survival, OS). RESULTS: The response and progression free survival of first-line chemotherapy affects the ORR, PFS and OS of second-line chemotherapy (ORR: CR/PR 15.4%, SD 10.1%, PD2.3%, p<0.001; PFS: CR/PR 3.80 months, SD 2.77 months, PD 2.03 months, p<0.001; OS: CR/PR 11.60 months, SD 10.33 months, PD 6.57 months, p=0.578, p<0.001, p<0.001, respectively). On multivariate analysis, better response to first-line therapy (CR/PR: HR=0.751, p=0.002; SD: HR=0.781, p=0.021) and progression within 3-6 months (HR=0.626, p<0.001), together with adenocarcinoma (HR=0.815, p=0.017), without liver metastasis (HR=0.541, p=0.001), never-smoker (HR=0.772, p=0.001), and ECOG PS 0-1 (HR=0.745, p=0.021) were predictors for good OS following second- line chemotherapy. CONCLUSIONS: Patients who responded to first-line chemotherapy had a better outcome after second-line therapy for advanced NSCLC, and the efficacy of first-line chemotherapy, period of progression, histology, liver metastasis, smoking status and ECOG PS were independent prognostic factors for OS.

Stimulus-sensitive polymeric nanoparticles and their applications as drug and gene carriers.

Polymeric nanoparticles are promising candidates as drug and gene carriers. Among polymeric nanoparticles, those that are responsive to internal or external stimuli are of greater interest because they allow more efficient delivery of therapeutics to pathological regions. Stimulus-sensitive polymeric nanoparticles have been fabricated based on numerous nanostructures, including micelles, vesicles, crosslinked nanoparticles, and hybrid nanoparticles. The changes in chemical or physical properties of polymeric nanoparticles that occur in response to single, dual, or multiple stimuli endow these nanoparticles with the ability to retain cargoes during circulation, target the pathological region, and release their cargoes after cell internalization. This Review focuses on the most recent developments in the preparation of stimulus-sensitive polymeric nanoparticles and their applications in drug and gene delivery.

Environmental pH-sensitive polymeric micelles for cancer diagnosis and targeted therapy.

The delivery and control over the release of hydrophobic imaging markers for cancer diagnosis or pharmaceutical agents for targeted therapy are of considerable interest. Nano-sized pH-sensitive polymeric micelles that rely on the enhanced permeability and retention (EPR) of vasculature and the low-pH microenvironment in cancer tissue are emerging as stimuli-responsive targeted therapies that can simultaneously release diagnostic and therapeutic agents into a cancerous region. This review focuses on the developments of pH-sensitive polymeric micelles and their biomedical applications in cancer diagnosis and targeted therapy.

A biodegradable polymersome with pH-tuning on-off membrane based on poly(ß-amino ester) for drug delivery.

A nanoscale biodegradable polymersome with pH-tuning on-off membrane is prepared via the self-assembly of poly(ß-amino ester)-based amphiphilic copolymers. The pH-sensitive polymersome-like vesicle structure includes two layers that can encapsulate either hydrophobic or hydrophilic therapeutic drugs at physiological pH 7.4. Below a pH of 7.0, the polymersome membrane forms tunnels through which the drug cargo can be rapidly released. The size and morphology of the polymersome are measured by transmission electron microscopy (TEM) and dynamic light scattering (DLS). The pH sensitivity is confirmed by fluorescence spectroscopy. The pH-sensitive drug-delivery polymersome provides a simple and powerful smart carrier for the delivery and controlled release of drugs.

The use of pH-sensitive positively charged polymeric micelles for protein delivery.

In this investigation, a nano-sized protein-encapsulated polymeric micelle was prepared by self-assembling human serum albumin (HSA) as a model protein and degradable block copolymer methoxy poly(ethylene glycol)-poly(ß-amino ester) (PEG-PAE) with piperidine and imidazole rings. From the zeta potential measurement, the protein-encapsulated polymeric micelle showed a pH-tuning charge conversion from neutral to positive when pH decreases from 7.8 to 6.2. It was envisioned that the pH-tunable positively charged polymeric micelle could enhance the protein delivery efficiency and, simultaneously, target to the pH-stimuli tissue, such as cancerous tissue or ischemia. The pH-dependent particle size and scattering intensity were also measured and showed 50-70 nm particle size. Consequently, the circular dichroism (CD) spectroscopy confirmed that the secondary structure of albumin was unaffected during the pH changing process. The in vitro cytotoxicity for the polymeric micelle was evaluated on MDA-MB-435 cell lines and no obvious toxicity could be observed when the polymer concentration was below 200 µg/mL. To assess the ability of this pH-tunable positively charged polymeric micelle as a vehicle for protein delivery to in vivo acidic tissues, we utilized a disease rat model of cerebral ischemia that produced an acidic tissue due to its pathologic condition. The rat was intravenously injected with the Cy5.5-labled albumin-encapsulated polymeric micelle. We found a gradual increase in fluorescence signals of the brain ischemic area, indicating that the pH-tuning positively charged protein-encapsulated polymeric micelle could be effective for targeting the acidic environment and diagnostic imaging.

Evaluation of pH-sensitive poly(ß-amino ester)-graft-poly(ethylene glycol) and its usefulness as a pH-sensor and protein carrier.

In this study, some possible biomedical applications of a pH-sensitive and amphiphilic copolymer as a pH sensor and protein delivery system are reported. PAE-g-PEG was used as a pH-sensitive polymer that can exhibit a sharp pH-dependent transition. Various fluorescent dyes including pyrene and RITC can be used to label the pH-sensitive polymer PAE-g-PEG, which was evaluated for protein encapsulation. pH-sensing was possible by observing excimer formation of the labeled pyrene via pH-dependent expansion of the polymeric chain. Also, it was confirmed that FITC-BSA could be entrapped in RITC-labeled pH-sensitive micelles of PAE-g-PEG by FRET. As a result, PAE-g-PEG can be a pH sensor and carrier for protein delivery.

pH-responsive polymeric micelle based on PEG-poly(ß-amino ester)/(amido amine) as intelligent vehicle for magnetic resonance imaging in detection of cerebral ischemic area.

A series of pH-responsive polymeric micelles is developed to act as intelligent carriers to deliver iron oxide (Fe(3)O(4)) nanoparticles and respond rapidly to an acidic stimuli environment for magnetic resonance imaging (MRI). The polymeric micelle can be self-assembled at physiological pH by a block copolymer, consisting of a hydrophilic methoxy poly(ethylene glycol) (PEG) and a pH-responsive poly(ß-amino ester)/(amido amine) block. Consequently, the Fe(3)O(4) nanoparticles can be well encapsulated into polymeric micelles due to the hydrophobic interaction, shielded by a PEG coronal shell. In an acidic environment, however, the pH-responsive component, which has ionizable tert-amino groups on its backbone, can become protonated to be soluble and release the hydrophobic Fe(3)O(4) nanoparticles. The Fe(3)O(4)-loaded polymeric micelle was measured by dynamic light scattering (DLS), superconducting quantum interference device (SQUID) and a 3.0T MRI scanner. To assess the ability of this MRI probe as a pH-triggered agent, we utilize a disease rat model of cerebral ischemia that produces acidic tissue due to its pathologic condition. We found gradual accumulation of Fe(3)O(4) nanoparticles in the brain ischemic area, indicating that the pH-triggered MRI probe may be effective for targeting the acidic environment and diagnostic imaging of pathologic tissue.