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1.  Efficient Gene Knockdown in Mouse Oocytes through Peptide Nanoparticle-Mediated SiRNA Transfection 
PLoS ONE  2016;11(3):e0150462.
The use of mouse oocytes as a model for studying female meiosis is very important in reproductive medicine. Gene knockdown by specific small interfering RNA (siRNA) is usually the first step in the study of the function of a target gene in mouse oocytes during in vitro maturation. Traditionally, the only way to introduce siRNA into mouse oocytes is through microinjection, which is certainly less efficient and strenuous than siRNA transfection in somatic cells. Recently, in research using somatic cells, peptide nanoparticle-mediated siRNA transfection has been gaining popularity over liposome nanoparticle-mediated methods because of its high efficiency, low toxicity, good stability, and strong serum compatibility. However, no researchers have yet tried transfecting siRNA into mouse oocytes because of the existence of the protective zona pellucida surrounding the oocyte membrane (vitelline membrane). We therefore tested whether peptide nanoparticles can introduce siRNA into mouse oocytes. In the present study, we showed for the first time that our optimized program can efficiently knock down a target gene with high specificity. Furthermore, we achieved the expected meiotic phenotypes after we knocked down a test unknown target gene TRIM75. We propose that peptide nanoparticles may be superior for preliminary functional studies of unknown genes in mouse oocytes.
doi:10.1371/journal.pone.0150462
PMCID: PMC4790955  PMID: 26974323
2.  Evaluation of Equivalent Keratometry Readings Obtained by Pentacam HR (High Resolution) 
PLoS ONE  2016;11(3):e0150121.
Purpose
To assess the repeatability of Equivalent Keratometry Readings (EKRs) obtained by the Pentacam HR (high resolution) in untreated and post-LASIK eyes, and to compare them with the keratometry (K) values obtained by other algorithms.
Methods
In this prospective study, 100 untreated eyes and 71 post-LASIK eyes were included. In the untreated group, each eye received 3 consecutive scans using the Pentacam HR, and EKR values in all central corneal zone, the true net power (Knet) and the simulated K (SimK) were obtained for each scan. In the post-LASIK group, each eye received subjective refraction and 3 consecutive scans with the Pentacam HR preoperatively. During the 3-month post-surgery exam, the same examinations and the use of an IOLMaster were conducted for each eye. The EKRs in all zone, the Knet, the mean K (Km) by IOLMaster and the K values by clinical history method (KCHM) were obtained. The repeatability of the EKRs was assessed by the within-subject standard deviation (Sw), 2.77Sw, coefficient of variation (CVw) and intraclass correlation coefficient (ICC). The bonferroni corrected multiple comparisons were performed to analyze the differences among the EKRs and K values calculated by other algorithms within the 2 groups. The 95% limits of agreement (LoA) were calculated.
Results
The EKR values in all central corneal zone were repeatable in both the untreated group (Sw≦0.19 D, 2.77Sw≦0.52 D, CVw≦1%, ICC≧0.978) and the post-LASIK group (Sw≦0.22 D, 2.77Sw≦0.62 D, CVw≦1%, ICC≧0.980). In the untreated group, the EKR in 4mm zone was close to SimK (P = 1.000), and the 95% LoA was (-0.13 to 0.15 D). The difference between Knet and SimK was -1.30±0.13 D (95% LoA -1.55 to -1.55 D, P<0.001). In the post-LASIK group, all the EKRs were significantly higher than KCHM (all P<0.001). The differences between the EKR in 4mm zone and KCHM, the EKR in 7mm zone and KCHM, Knet and KCHM, Km and KCHM, SimK and Knet were 0.64±0.50 D (95% LoA, -0.33 to 1.62 D), 1.77±0.88 D (95% LoA, 0.04 to 3.51 D), -0.98±0.48 D (95% LoA, -1.92 to -0.04 D), 0.64±0.53 D (95% LoA, -0.40 to 1.68 D), and 1.73±0.20 D (95% LoA, 1.33 to 2.13 D), respectively.
Conclusions
The EKRs obtained by the Pentacam HR were repeatable in both untreated eyes and post-LASIK eyes. Compared to the total corneal power obtained by the clinical history method, the EKR values generally overestimated the total corneal power in post-LASIK eyes. So, further calibrations for the EKR values should be conducted, before they were used for the total corneal power assessment in post-LASIK eyes.
doi:10.1371/journal.pone.0150121
PMCID: PMC4780706  PMID: 26950834
3.  Different cucumber CsYUC genes regulate response to abiotic stresses and flower development 
Scientific Reports  2016;6:20760.
The phytohormone auxin is essential for plant growth and development, and YUCCA (YUC) proteins catalyze a rate-limiting step for endogenous auxin biosynthesis. Despite YUC family genes have been isolated from several species, systematic expression analyses of YUCs in response to abiotic stress are lacking, and little is known about the function of YUC homologs in agricultural crops. Cucumber (Cucumis sativus L.) is a world cultivated vegetable crop with great economical and nutritional value. In this study, we isolated 10 YUC family genes (CsYUCs) from cucumber and explored their expression pattern under four types of stress treatments. Our data showed that CsYUC8 and CsYUC9 were specifically upregulated to elevate the auxin level under high temperature. CsYUC10b was dramatically increased but CsYUC4 was repressed in response to low temperature. CsYUC10a and CsYUC11 act against the upregulation of CsYUC10b under salinity stress, suggesting that distinct YUC members participate in different stress response, and may even antagonize each other to maintain the proper auxin levels in cucumber. Further, CsYUC11 was specifically expressed in the male flower in cucumber, and enhanced tolerance to salinity stress and regulated pedicel and stamen development through auxin biosynthesis in Arabidopsis.
doi:10.1038/srep20760
PMCID: PMC4746583  PMID: 26857463
4.  The Peripheral Blood Neutrophil-To-Lymphocyte Ratio Is Superior to the Lymphocyte-To-Monocyte Ratio for Predicting the Long-Term Survival of Triple-Negative Breast Cancer Patients 
PLoS ONE  2015;10(11):e0143061.
Purpose
The peripheral hematologic parameters of patients can be prognostic for many malignant tumors, including breast cancer, although their value has not been investigated among the different molecular subtypes of breast cancer. The purpose of this study was to examine the prognostic significance of the neutrophil-to-lymphocyte ratio (NLR) and the lymphocyte-to-monocyte ratio (LMR) in different molecular subtypes of breast cancer.
Methods
A retrospective cohort of 1570 operable breast cancer patients was recruited between January 2000 and December 2010. The counts of peripheral neutrophils, lymphocytes, monocytes and platelets were collected and applied to calculate the NLR and the LMR. Univariate and multivariate Cox proportional hazard analyses were used to assess the relationship of the NLR and the LMR with disease-free survival (DFS) and overall survival (OS) in all patients and triple negative breast cancer (TNBC) patients.
Results
Univariate analysis revealed that lower NLR (≤2.0) and higher LMR (>4.8) were significantly associated with superior DFS in all patients (NLR, P = 0.005; LMR, P = 0.041) and in TNBC patients (NLR, p = 0.007; LMR, P = 0.011). However, multivariate analysis revealed that only lower NLR was a significant independent predictor of superior DFS and OS in all breast cancer patients (DFS, HR = 1.50 95% CI: 1.14–1.97, P = 0.004; OS, HR = 1.63, 95% CI: 1.07–2.49, P = 0.022) and in TNBC patients (DFS, HR = 2.58, 95% CI: 1.23–5.42, P = 0.012; OS, HR = 3.05, 95% CI: 1.08–8.61, P = 0.035). Both univariate and multivariate analysis revealed that neither the NLR nor the LMR significantly predicted DFS and OS among the patients with other molecular subtypes of breast cancer.
Conclusions
A higher pretreatment peripheral NLR significantly and independently indicated a poor prognosis for breast cancer and TNBC, and this measurement exhibited greater prognostic value than a lower LMR. The NLR was not a prognostic factor for other breast cancer subtypes.
doi:10.1371/journal.pone.0143061
PMCID: PMC4666347  PMID: 26580962
5.  Targeted Delivery of Anticancer Agents via a Dual Function Nanocarrier with an Interfacial Drug-Interactive Motif 
Biomacromolecules  2014;15(11):4326-4335.
We have developed a dual-function drug carrier, polyethylene glycol (PEG)-derivatized farnesylthiosalicylate (FTS). Here we report that incorporation of a drug-interactive motif (Fmoc) into PEG5k–FTS2 led to further improvement in both drug loading capacity and formulation stability. Doxorubicin (DOX) formulated in PEG5k–Fmoc–FTS2 showed sustained release kinetics slower than those of DOX loaded in PEG5k–FTS2. The maximum tolerated dose of DOX- or paclitaxel (PTX)-loaded PEG5k–Fmoc–FTS2 was significantly higher than that of the free drug. Pharmacokinetics and biodistribution studies showed that DOX/PEG5k–Fmoc–FTS2 mixed micelles were able to retain DOX in the bloodstream for a significant amount of time and efficiently deliver the drug to tumor sites. More importantly, drug (DOX or PTX)-loaded PEG5k–Fmoc–FTS2 led to superior antitumor activity over other treatments including drugs formulated in PEG5k–FTS2 in breast cancer and prostate cancer models. Our improved dual function carrier with a built-in drug-interactive motif represents a simple and effective system for targeted delivery of anticancer agents.
doi:10.1021/bm501339j
PMCID: PMC4229023  PMID: 25325795
6.  Comorbidity of poor sleep and primary headaches among nursing staff in north China 
Background
Sleep disorders and primary headaches are both more prevalent among nursing staff than in the general population. However, there have been no reports about the comorbidity of poor sleep and primary headaches among nursing staff.
Methods
Stratified random cluster sampling was used to select 1102 nurses from various departments in three hospitals in north China. Sleep quality was assessed with the Pittsburgh Sleep Quality Index (PSQI). The diagnosis of primary headaches including migraine, tension-type headache (TTH), and chronic daily headache (CDH) was based on the International Classification of Headache Disorders, 3rd edition (beta version) (ICHD-3-beta).
Results
The response rate was 93 %. Among 1023 nurses, the prevalence of poor sleep was 56.7 %. Of these, 315 nurses (34.13 %) had poor sleep comorbid with primary headaches. The prevalence of poor sleep in the groups with CDH (82.1 %), migraine (78.9 %), and TTH (59.0 %) was significantly higher than that in the group without headaches (47.3 %) (all P < 0.05). Multivariate logistic regression revealed that rotating shifts and suffering headache were independent risk factors for poor sleep. Also, the 1-year prevalence of the three types of primary headache was significantly increased in the poor sleep group (migraine: 21.2 % vs. 7.2 %; TTH: 27.9 % vs. 24.9 %; CDH: 4.1 % vs. 1.1 %; P < 0.05). Compared with normal sleepers, nurses with poor sleep were 1.72 times more likely to have severe headache (OR: 1.72, 95 % CI: 1.14–2.57).
Conclusion
Comorbidity of poor sleep and primary headaches among nursing staff is common. Therefore, sleep quality should be carefully evaluated in nurses with primary headaches.
doi:10.1186/s10194-015-0571-z
PMCID: PMC4598334  PMID: 26449228
Comorbidity; Poor sleep; Primary Headache; Migraine; Tension-type headache; Chronic daily headache; Nursing staff
7.  Fmoc-Conjugated PEG-Vitamin E2 Micelles for Tumor-Targeted Delivery of Paclitaxel: Enhanced Drug-Carrier Interaction and Loading Capacity 
The AAPS Journal  2014;16(6):1282-1291.
The purpose of this study is to develop an improved drug delivery system for enhanced paclitaxel (PTX) loading capacity and formulation stability based on PEG5K-(vitamin E)2 (PEG5K-VE2) system. PEG5K-(fluorenylmethoxycarbonyl)-(vitamin E)2 (PEG5K-FVE2) was synthesized using lysine as the scaffold. PTX-loaded PEG5K-FVE2 micelles were prepared and characterized. Fluorescence intensity of Fmoc in the micelles was measured as an indicator of drug-carrier interaction. Cytotoxicity of the micelle formulations was tested on various tumor cell lines. The therapeutic efficacy and toxicity of PTX-loaded micelles were investigated using a syngeneic mouse model of breast cancer (4T1.2). Our data suggest that the PEG5K-FVE2 micelles have a low CMC value of 4 μg/mL and small sizes (~60 nm). The PTX loading capacity of PEG5K-FVE2 micelles was much higher than that of PEG5K-VE2 micelles. The Fmoc/PTX physical interaction was clearly demonstrated by a fluorescence quenching assay. PTX-loaded PEG5K-FVE2 micelles exerted more potent cytotoxicity than free PTX or Taxol formulation in vitro. Finally, intravenous injection of PTX-loaded PEG5K-FVE2 micelles showed superior anticancer activity compared with PEG5K-VE2 formulation with minimal toxicity in a mouse model of breast cancer. In summary, incorporation of a drug-interactive motif (Fmoc) into PEG5K-VE2 micelles represents an effective strategy to improve the micelle formulation for the delivery of PTX.
Electronic supplementary material
The online version of this article (doi:10.1208/s12248-014-9651-2) contains supplementary material, which is available to authorized users.
doi:10.1208/s12248-014-9651-2
PMCID: PMC4389742  PMID: 25193267
drug delivery; drug-interactive motif; micelles; paclitaxel; vitamin E derivative
8.  HANABA TARANU regulates the shoot apical meristem and leaf development in cucumber (Cucumis sativus L.) 
Journal of Experimental Botany  2015;66(22):7075-7087.
Highlight
Functional analysis of cucumber CsHAN1 showed that it regulates meristem development through WUSCHEL and SHOOT MERISTEMLESS pathways, and mediates leaf development through a complicated gene regulatory network in cucumber.
The shoot apical meristem (SAM) is essential for continuous organogenesis in higher plants, while the leaf is the primary source organ and the leaf shape directly affects the efficiency of photosynthesis. HANABA TARANU (HAN) encodes a GATA3-type transcription factor that functions in floral organ development, SAM organization, and embryo development in Arabidopsis, but is involved in suppressing bract outgrowth and promoting branching in grass species. Here the function of the HAN homologue CsHAN1 was characterized in cucumber, an important vegetable with great agricultural and economic value. CsHAN1 is predominantly expressed at the junction of the SAM and the stem, and can partially rescue the han-2 floral organ phenotype in Arabidopsis. Overexpression and RNAi of CsHAN1 transgenic cucumber resulted in retarded growth early after embryogenesis and produced highly lobed leaves. Further, it was found that CsHAN1 may regulate SAM development through regulating the WUSCHEL (WUS) and SHOOT MERISTEMLESS (STM) pathways, and mediate leaf development through a complicated gene regulatory network in cucumber.
doi:10.1093/jxb/erv409
PMCID: PMC4765787  PMID: 26320238
CsHAN; CsSTM; CsWUS; cucumber; leaf development; shoot apical meristem.
9.  Fluid Shear Stress Upregulates E-Tmod41 via miR-23b-3p and Contributes to F-Actin Cytoskeleton Remodeling during Erythropoiesis 
PLoS ONE  2015;10(8):e0136607.
The membrane skeleton of mature erythrocyte is formed during erythroid differentiation. Fluid shear stress is one of the main factors that promote embryonic hematopoiesis, however, its effects on erythroid differentiation and cytoskeleton remodeling are unclear. Erythrocyte tropomodulin of 41 kDa (E-Tmod41) caps the pointed end of actin filament (F-actin) and is critical for the formation of hexagonal topology of erythrocyte membrane skeleton. Our study focused on the regulation of E-Tmod41 and its role in F-actin cytoskeleton remodeling during erythroid differentiation induced by fluid shear stress. Mouse erythroleukemia (MEL) cells and embryonic erythroblasts were subjected to fluid shear stress (5 dyn/cm2) and erythroid differentiation was induced in both cells. F-actin content and E-Tmod41 expression were significantly increased in MEL cells after shearing. E-Tmod41 overexpression resulted in a significant increase in F-actin content, while the knockdown of E-Tmod41 generated the opposite result. An E-Tmod 3’UTR targeting miRNA, miR-23b-3p, was found suppressed by shear stress. When miR-23b-3p level was overexpressed / inhibited, both E-Tmod41 protein level and F-actin content were reduced / augmented. Furthermore, among the two alternative promoters of E-Tmod, PE0 (upstream of exon 0), which mainly drives the expression of E-Tmod41, was found activated by shear stress. In conclusion, our results suggest that fluid shear stress could induce erythroid differentiation and F-actin cytoskeleton remodeling. It upregulates E-Tmod41 expression through miR-23b-3p suppression and PE0 promoter activation, which, in turn, contributes to F-actin cytoskeleton remodeling.
doi:10.1371/journal.pone.0136607
PMCID: PMC4550387  PMID: 26308647
10.  Reduction-Sensitive Dual Functional Nanomicelles for Improved Delivery of Paclitaxel 
Bioconjugate Chemistry  2014;25(9):1689-1696.
We have developed a dual-functional nanocarrier composed of a hydrophilic polyethylene glycol (PEG) and a hydrophobic farnesylthiosalicylate (FTS, a nontoxic Ras antagonist), which is effective in delivery of hydrophobic anticancer drug, paclitaxel (PTX). To facilitate the retention of the therapeutic activity of the carrier, FTS was coupled to PEG via a reduction-sensitive disulfide linkage (PEG5k-S-S-FTS2). PEG5k-S-S-FTS2 conjugate formed uniform micelles with very small size (∼30 nm) and the hydrophobic drug PTX could be readily incorporated into the micelles. Interestingly, inclusion of a disulfide linkage into the PEG5k-FTS2 micellar system resulted in a 4-fold decrease in the critical micelle concentration (CMC). In addition, the PTX loading capacity and colloidal stability of PTX-loaded micelles were improved. HPLC-MS showed that parent FTS could be more effectively released from PEG5k-S-S-FTS2 conjugate in tumor cells/tissues compared to PEG5k-FTS2 conjugate in vitro and in vivo. PEG5k-S-S-FTS2 exhibited a higher level of cytotoxicity toward tumor cells than PEG5k-FTS2 without a disulfide linkage. Furthermore, PTX-loaded PEG5k-S-S-FTS2 micelles were more effective in inhibiting the proliferation of cultured tumor cells compared to Taxol and PTX loaded in PEG5k-FTS2 micelles. More importantly, PTX-loaded PEG5k-S-S-FTS2 micelles demonstrated superior antitumor activity compared to Taxol and PTX formulated in PEG5k-FTS2 micelles in an aggressive murine breast cancer model (4T1.2).
doi:10.1021/bc500292j
PMCID: PMC4166038  PMID: 25121577
11.  A PEG-Fmoc conjugate as a nanocarrier for paclitaxel 
Biomaterials  2014;35(25):7146-7156.
We report here that a simple, well-defined, and easy-to-scale up nanocarrier, PEG5000-lysyl-(α-Fmoc-ε-t-Boc-lysine)2 conjugate (PEG-Fmoc), provides high loading capacity, excellent formulation stability and low systemic toxicity for paclitaxel (PTX), a first-line chemotherapeutic agent for various types of cancers. 9-Fluorenylmethoxycarbonyl (Fmoc) was incorporated into the nanocarrier as a functional building block to interact with drug molecules. PEG-Fmoc was synthesized via a three-step synthetic route, and it readily interacted with PTX to form mixed nanomicelles of small particle size (25–30 nm). The PTX loading capacity was about 36%, which stands well among the reported micellar systems. PTX entrapment in this micellar system is achieved largely via an Fmoc/PTX π-π stacking interaction, which was demonstrated by fluorescence quenching studies and 13C-NMR. PTX formulated in PEG-Fmoc micelles demonstrated sustained release kinetics, and in vivo distribution study via near infrared fluorescence imaging demonstrated an effective delivery of Cy5.5-labled PTX to tumor sites. The maximal tolerated dose for PTX/PEG-Fmoc (MTD > 120 mg PTX/kg) is higher than those for most reported PTX formulations, and in vivo therapeutic study exhibited a significantly improved antitumor activity than Taxol, a clinically used formulation of PTX. Our system may hold promise as a simple, safe, and effective delivery system for PTX with a potential for rapid translation into clinical study.
doi:10.1016/j.biomaterials.2014.04.108
PMCID: PMC4102141  PMID: 24856103
micelle; 9-Fluorenylmethoxycarbonyl; drug-carrier interaction; paclitaxel; drug delivery; cancer therapy
12.  Extracellular polymeric substance from Aphanizomenon flos-aquae induces apoptosis via the mitochondrial pathway in A431 human epidermoid carcinoma cells 
Extracellular polymeric substance (EPS) is a substance secreted during algal growth, which has been found to have numerous health-promoting effects. In the present study, A431 human epidermoid carcinoma cells were selected as target cells and cultivated in vitro as an experimental model to investigate the anti-cancer effect of extracellular polymeric substances from Aphanizomenon flos-aquae (EPS-A) and the possible underlying mechanism. Apoptosis- and cell cycle-associated molecules as well as the mitochondrial membrane potential of the cells were quantified using flow cytometry (FCM). FCM showed that EPS-A induced cell cycle arrest, which led to a loss of mitochondrial function of the A431 cells and an increase in necrotic and late apoptotic cells. In order to evaluate the apoptosis and cell viability, acridine orange/ethidium bromide staining was used, morphological changes were observed using fluorescence microscopy and typical apoptotic characteristics were observed. Following treatment with a high dose of EPS-A, transmission electron microscopy showed nuclear fragmentation, chromosome condensation, cell shrinkage and expansion of the endoplasmic reticulum; apoptotic bodies were also observed. In conclusion, EPS-A caused cell cycle arrest, stimulated cell apoptosis via the mitochondrial pathway and exhibited important anti-cancer activity.
doi:10.3892/etm.2015.2644
PMCID: PMC4533141  PMID: 26622416
extracellular polymeric substances; apoptosis; anti-cancer; Aphanizomenon flos-aquae; human epidermoid carcinoma
13.  PEG-Farnesyl Thiosalicylic Acid Telodendrimer Micelles as an Improved Formulation for Targeted Delivery of Paclitaxel 
Molecular Pharmaceutics  2014;11(8):2807-2814.
We have recently designed and developed a dual-functional drug carrier that is based on poly(ethylene glycol) (PEG)-derivatized farnesylthiosalicylate (FTS, a nontoxic Ras antagonist). PEG5K-FTS2 readily form micelles (20–30 nm) and hydrophobic drugs such as paclitaxel (PTX) could be effectively loaded into these micelles. PTX formulated in PEG5K-FTS2 micelles showed an antitumor activity that was more efficacious than Taxol in a syngeneic mouse model of breast cancer (4T1.2). In order to further improve our PEG-FTS micellar system, four PEG-FTS conjugates were developed that vary in the molecular weight of PEG (PEG2K vs PEG5K) and the molar ratio of PEG/FTS (1/2 vs 1/4) in the conjugates. These conjugates were characterized including CMC, drug loading capacity, stability, and their efficacy in delivery of anticancer drug PTX to tumor cells in vitro and in vivo. Our data showed that the conjugates with four FTS molecules were more effective than the conjugates with two molecules of FTS and that FTS conjugates with PEG5K were more effective than the counterparts with PEG2K in forming stable mixed micelles. PTX formulated in PEG5K-FTS4 micelles was the most effective formulation in inhibiting the tumor growth in vivo.
doi:10.1021/mp500181x
PMCID: PMC4123940  PMID: 24987803
paclitaxel; farnesyl thiosalicylic acid; dual function; nanomicelles; targeted delivery
14.  Inhibition of a novel fibrogenic factor Tl1a reverses established colonic fibrosis 
Mucosal immunology  2014;7(6):1492-1503.
Intestinal fibrostenosis is among the hallmarks of severe Crohn’s disease. Patients with certain TNFSF15 (gene name for TL1A) variants over-express TL1A and have a higher risk of developing strictures in the small intestine. Additionally, sustained Tl1a expression in mice leads to small and large intestinal fibrostenosis under colitogenic conditions. The aim of this study was to determine whether established murine colonic fibrosis could be reversed with Tl1a antibody. Treatment with neutralizing Tl1a antibody reversed colonic fibrosis back to the original pre-inflamed levels, potentially as result of lowered expression of connective tissue growth factor (Ctgf), Il31Ra, transforming growth factor (Tgf) β1 and insulin-like growth factor-1 (Igf1). Additionally, blocking Tl1a function by either neutralizing Tl1a antibody or deletion of death domain receptor 3 (Dr3) reduced the number of fibroblasts and myofibroblasts, the primary cell types that mediate tissue fibrosis. Primary intestinal myofibroblasts expressed Dr3 and functionally responded to direct Tl1a signaling by increasing collagen and Il31Ra expression. These data demonstrated a direct role for TL1A-DR3 signaling in tissue fibrosis and that modulation of TL1A-DR3 signaling could inhibit gut fibrosis.
doi:10.1038/mi.2014.37
PMCID: PMC4205266  PMID: 24850426
Fibrosis; TL1A; DR3
15.  Targeted Delivery of Curcumin to Tumors via PEG-Derivatized FTS-Based Micellar System 
The AAPS Journal  2014;16(3):600-608.
Curcumin and S-trans, trans-farnesylthiosalicylic acid (FTS) are two promising anticancer agents. In this study, we demonstrated that the two agents exerted significant synergy in antitumor activity in various types of cancer cells with combination indices ranging from 0.46 to 0.98 (a value of less than unity indicates synergism). We have further shown that synergistic-targeted co-delivery of the two agents can be achieved via formulating curcumin in polyethylene glycol (PEG)-derivatized FTS-based nanomicellar system. Curcumin formulated in PEG-FTS micelles had small size of around 20 nm. The nanomicellar curcumin demonstrated enhanced cytotoxicity towards several cancer cell lines in vitro. Intravenous application of curcumin-loaded micelle (20 mg kg−1 curcumin) led to a significantly more effective inhibition of tumor growth in a syngeneic mouse breast cancer model (4T1.2) than curcumin formulated in Cremophor/EL (P < 0.05).
Electronic supplementary material
The online version of this article (doi:10.1208/s12248-014-9595-6) contains supplementary material, which is available to authorized users.
doi:10.1208/s12248-014-9595-6
PMCID: PMC4012035  PMID: 24706375
curcumin; dual–functional carrier; micelles; synergy; S-trans, trans-farnesylthiosalicylic acid
16.  Human colon carcinogenesis is associated with increased interleukin-17-driven inflammatory responses 
Inflammation is known to contribute to carcinogenesis in human colorectal cancer. Proinflammatory cytokine interleukin-17 (IL-17 or IL-17A) has been shown to play a critical role in colon carcinogenesis in mouse models. However, few studies have investigated IL-17A in human colon tissues. In the present study, we assessed IL-17-driven inflammatory responses in 17 cases of human colon adenocarcinomas, 16 cases of human normal colon tissues adjacent to the resected colon adenocarcinomas, ten cases of human ulcerative colitis tissues from biopsies, and eight cases of human colon polyps diagnosed as benign adenomas. We found that human colon adenocarcinomas contained the highest levels of IL-17A cytokine, which was significantly higher than the IL-17A levels in the adenomas, ulcerative colitis, and normal colon tissues (P<0.01). The levels of IL-17 receptor A (IL-17RA) were also the highest in human colon adenocarcinomas, followed by adenomas and ulcerative colitis. The increased levels of IL-17A and IL-17RA were accompanied with increased IL-17-driven inflammatory responses, including activation of extracellular signal-regulated kinase (ERK)1/2 and c-Jun N-terminal kinase (JNK) pathways, increase in expression of matrix metalloproteinase (MMP)9, MMP7, MMP2, B-cell lymphoma (Bcl-2), and cyclin D1, decrease in Bcl-2-associated X protein (BAX) expression, and increase in vascular endothelial growth factor (VEGF) and VEGF receptor (VEGFR) expression that were associated with increased angiogenesis. These findings suggest that IL-17 and its signaling pathways appear as promising new targets in the design and development of drugs for cancer prevention and treatment, particularly in colorectal cancer.
doi:10.2147/DDDT.S79431
PMCID: PMC4370916  PMID: 25834404
colitis; colorectal cancer; inflammation; IL-17
17.  The prevalence of primary headache disorders and their associated factors among nursing staff in North China 
Background
Epidemiological data on the prevalence of headache in nursing staff in Mainland China are lacking. We therefore performed a study to assess the prevalence of headache, and factors associated with headaches, in nursing staff in three hospitals in North China.
Methods
Stratified random cluster sampling was used to select 1102 nurses from various departments in three hospitals. A structured questionnaire was used to collect epidemiological data, headache characteristics and associated factors.
Results
The response rate was 93.0%. Among nursing staff, the 1-year prevalence of primary headache disorders was 45.3%, of migraine 14.8% (migraine with aura 3.4%, migraine without aura 11.4%), of tension-type headache (TTH) 26.2%, of chronic daily headache (CDH) 2.7%. Multivariate analysis showed that seniority (≥5 years) was a risk factor for migraine (OR 2.280), obesity (BMI ≥ 25) was a risk factor for TTH and CDH (OR 1.684 and 3.184), and age (≥40 years) was a risk factor for CDH (OR 8.455). Nurses working in internal medicine were more likely to suffer CDH than those in other departments. Working a greater number of night shifts was also associated with increased prevalence of headache.
Conclusion
The prevalence of primary headache disorders in nurses is higher than that in the general population in China, and occupational factors may play an important role. Therefore, the prevalence of headache in nurses should be a focus of attention, and coping strategies should be provided. Such measures could contribute to improving patient care.
doi:10.1186/1129-2377-16-4
PMCID: PMC4405508  PMID: 25582043
Prevalence; Headache; Migraine; Tension-type headache; Chronic daily headache; Nursing staff
18.  Design and Evaluation of a PEGylated Lipopeptide Equipped with Drug-Interactive Motifs as an Improved Drug Carrier 
The AAPS Journal  2013;16(1):114-124.
Micelles are attractive delivery systems for hydrophobic drugs due to their small size and the ease of application. However, the limited drug loading capacity and the intrinsic poor stability of drug-loaded formulations represent two major issues for some micellar systems. In this study, we designed and synthesized a micelle-forming PEG-lipopeptide conjugate with two Fmoc groups located at the interfacial region, and two oleoyl chains as the hydrophobic core. The significance of Fmoc groups as a broadly applicable drug-interactive motif that enhances the carrier–drug interaction was examined using eight model drugs of diverse structures. Compared with an analogue without carrying a Fmoc motif, PEG5000-(Fmoc-OA)2 demonstrated a lower value of critical micelle concentration and three-fold increases of loading capacity for paclitaxel (PTX). These micelles showed tubular structures and small particle sizes (∼70 nm), which can be lyophilized and readily reconstituted with water without significant changes in particle sizes. Fluorescence quenching study illustrated the Fmoc/PTX π–π stacking contributes to the carrier/PTX interaction, and drug-release study demonstrated a much slower kinetics than Taxol, a clinically used PTX formulation. PTX/PEG5000-(Fmoc-OA)2 mixed micelles exhibited higher levels of cytotoxicity than Taxol in several cancer cell lines and more potent inhibitory effects on tumor growth than Taxol in a syngeneic murine breast cancer model (4T1.2). We have further shown that seven other drugs can be effectively formulated in PEG5000-(Fmoc-OA)2 micelles. Our study suggests that micelle-forming PEG-lipopeptide surfactants with interfacial Fmoc motifs may represent a promising formulation platform for a broad range of drugs with diverse structures.
Electronic supplementary material
The online version of this article (doi:10.1208/s12248-013-9536-9) contains supplementary material, which is available to authorized users.
doi:10.1208/s12248-013-9536-9
PMCID: PMC3889538  PMID: 24281690
drug-interactive motif; micelle; paclitaxel; slow release
19.  Nanomicellar carriers for targeted delivery of anticancer agents 
Therapeutic delivery  2014;5(1):53-68.
Clinical application of anticancer drugs is limited by problems such as low water solubility, lack of tissue-specificity and toxicity. Formulation development represents an important approach to these problems. Among the many delivery systems studied, polymeric micelles have gained considerable attention owing to ease in preparation, small sizes (10–100 nm), and ability to solubilize water-insoluble anticancer drugs and accumulate specifically at the tumors. This article provides a brief review of several promising micellar systems and their applications in tumor therapy. The emphasis is placed on the discussion of the authors’ recent work on several nanomicellar systems that have both a delivery function and antitumor activity, named dual-function drug carriers.
doi:10.4155/tde.13.135
PMCID: PMC3913259  PMID: 24341817
20.  A Simple Repeat Polymorphism in the MITF-M Promoter Is a Key Regulator of White Spotting in Dogs 
PLoS ONE  2014;9(8):e104363.
The white spotting locus (S) in dogs is colocalized with the MITF (microphtalmia-associated transcription factor) gene. The phenotypic effects of the four S alleles range from solid colour (S) to extreme white spotting (sw). We have investigated four candidate mutations associated with the sw allele, a SINE insertion, a SNP at a conserved site and a simple repeat polymorphism all associated with the MITF-M promoter as well as a 12 base pair deletion in exon 1B. The variants associated with white spotting at all four loci were also found among wolves and we conclude that none of these could be a sole causal mutation, at least not for extreme white spotting. We propose that the three canine white spotting alleles are not caused by three independent mutations but represent haplotype effects due to different combinations of causal polymorphisms. The simple repeat polymorphism showed extensive diversity both in dogs and wolves, and allele-sharing was common between wolves and white spotted dogs but was non-existent between solid and spotted dogs as well as between wolves and solid dogs. This finding was unexpected as Solid is assumed to be the wild-type allele. The data indicate that the simple repeat polymorphism has been a target for selection during dog domestication and breed formation. We also evaluated the significance of the three MITF-M associated polymorphisms with a Luciferase assay, and found conclusive evidence that the simple repeat polymorphism affects promoter activity. Three alleles associated with white spotting gave consistently lower promoter activity compared with the allele associated with solid colour. We propose that the simple repeat polymorphism affects cooperativity between transcription factors binding on either flanking sides of the repeat. Thus, both genetic and functional evidence show that the simple repeat polymorphism is a key regulator of white spotting in dogs.
doi:10.1371/journal.pone.0104363
PMCID: PMC4130573  PMID: 25116146
21.  Computational morphodynamics of plants: integrating development over space and time 
Preface
The emerging field of computational morphodynamics aims to understand the changes that occur in space and time during development by combining three technical strategies: live imaging to observe development as it happens, image processing and analysis to extract quantitative information, and computational modelling to express and test time-dependent hypotheses. The strength of the field comes from the iterative and combined use of these techniques, which has provided important insight into plant development.
doi:10.1038/nrm3079
PMCID: PMC4128830  PMID: 21364682
22.  Transcriptome profiling reveals roles of meristem regulators and polarity genes during fruit trichome development in cucumber (Cucumis sativus L.) 
Journal of Experimental Botany  2014;65(17):4943-4958.
Summary
Cucumber fruit spine is multicellular and non-branched with no endoreduplication. Spines in the tbh mutant were tiny and branched. Meristem regulators and polarity genes regulate spine development in cucumber.
Trichomes are epidermal hair-like structures that function in plant defence against biotic and abiotic stresses. Extensive studies have been performed on foliar trichomes development in Arabidopsis and tomato, but the molecular mechanism of fruit trichome formation remains elusive. Cucumber fruit is covered with trichomes (spines) that directly affect the appearance and quality of cucumber products. Here, we characterized the fruit spine development in wild-type (WT) cucumber and a spontaneous mutant, tiny branched hair (tbh). Our data showed that the cucumber trichome was multicellular and non-glandular, with malformed organelles and no endoreduplication. Fruit spine development was generally homogenous and marked by a rapid base expansion stage. Trichomes in the tbh mutant were tiny and branched, with increased density and aberrant cell shape. Transcriptome profiling indicated that meristem-related genes were highly enriched in the upregulated genes in the tbh versus the WT, as well as in WT spines after versus before base expansion, and that polarity regulators were greatly induced during spine base expansion. Quantitative reverse transcription PCR and in situ hybridization confirmed the differential expression of CUP-SHAPED COTYLEDON3 (CUC3) and SHOOT MERISTEMLESS (STM) during spine development. Therefore, cucumber trichomes are morphologically different from those of Arabidopsis and tomato, and their development may be regulated by a distinct pathway involving meristem genes and polarity regulators.
doi:10.1093/jxb/eru258
PMCID: PMC4144775  PMID: 24962999
Cucumber; fruit spine; meristem regulator; polarity transcriptome; trichome.
23.  Clinical Predictive Models for Chemotherapy-Induced Febrile Neutropenia in Breast Cancer Patients: A Validation Study 
PLoS ONE  2014;9(6):e96413.
Background
Predictive models for febrile neutropenia (FN) would be informative for physicians in clinical decision making. This study aims to validate a predictive model (Jenkin’s model) that comprises pretreatment hematological parameters in early-stage breast cancer patients.
Patients and Methods
A total of 428 breast cancer patients who received neoadjuvant/adjuvant chemotherapy without any prophylactic use of colony-stimulating factor were included. Pretreatment absolute neutrophil counts (ANC) and absolute lymphocyte counts (ALC) were used by the Jenkin’s model to assess the risk of FN. In addition, we modified the threshold of Jenkin’s model and generated Model-A and B. We also developed Model-C by incorporating the absolute monocyte count (AMC) as a predictor into Model-A. The rates of FN in the 1st chemotherapy cycle were calculated. A valid model should be able to significantly identify high-risk subgroup of patients with FN rate >20%.
Results
Jenkin’s model (Predicted as high-risk when ANC≦3.1*10∧9/L;ALC≦1.5*10∧9/L) did not identify any subgroups with significantly high risk (>20%) of FN in our population, even if we used different thresholds in Model-A(ANC≦4.4*10∧9/L;ALC≦2.1*10∧9/L) or B(ANC≦3.8*10∧9/L;ALC≦1.8*10∧9/L). However, with AMC added as an additional predictor, Model-C(ANC≦4.4*10∧9/L;ALC≦2.1*10∧9/L; AMC≦0.28*10∧9/L) identified a subgroup of patients with a significantly high risk of FN (23.1%).
Conclusions
In our population, Jenkin’s model, cannot accurately identify patients with a significant risk of FN. The threshold should be changed and the AMC should be incorporated as a predictor, to have excellent predictive ability.
doi:10.1371/journal.pone.0096413
PMCID: PMC4063732  PMID: 24945817
24.  Transcriptional and Epigenetic Dynamics During Specification of Human Embryonic Stem Cells 
Cell  2013;153(5):1149-1163.
Differentiation of human embryonic stem cells (hESCs) provides a unique opportunity to study the regulatory mechanisms that facilitate cellular transitions in a human context. To that end, we performed comprehensive transcriptional and epigenetic profiling of populations derived through directed differentiation of hESCs representing each of the three embryonic germ layers. Integration of whole genome bisulfite sequencing, chromatin immunoprecipitation-sequencing and RNA-sequencing reveals unique events associated with specification towards each lineage. Dynamic alterations in DNA methylation and H3K4me1 are evident at putative distal regulatory elements bound by pluripotency factors or activated in specific lineages. In addition, we identified germ layer-specific H3K27me3 enrichment at sites exhibiting high DNA methylation in the undifferentiated state. A better understanding of these initial specification events will facilitate identification of deficiencies in current approaches leading to more faithful differentiation strategies as well as provide insights into the rewiring of human regulatory programs during cellular transitions.
doi:10.1016/j.cell.2013.04.037
PMCID: PMC3709577  PMID: 23664763
25.  Oncostatin M receptor β and cysteine/histidine-rich 1 are biomarkers of the response to erythropoietin in hemodialysis patients 
Kidney international  2010;79(5):546-554.
Biomarkers that evaluate the response to erythropoietic-stimulating agents largely measure inflammation and iron availability. While these are important factors in modifying an individual’s response to these agents, they do not address all aspects of a poor response. To clarify this, we isolated peptides in the serum of good and poor responders to erythropoietin in order to identify biomarkers of stimulating agent response. Ninety-one candidate biomarker targets were identified and characterized using mass spectrometry, of which tandem mass spectroscopy provided partial amino-acid sequence information of 17 different peptides for 16 peptide masses whose abundance significantly differed between poor and good responders. The analysis concluded that three peptides associated with a poor response were derived from oncostatin M receptor β (OSMRβ). The 13 serum peptides associated with a good response were derived from fibrinogen α and β, coagulation factor XIII, complement C3, and cysteine/histidine rich 1(CYHR1). Poor response was most strongly associated with the OSMRβ fragment with the largest molecular weight, while a good response was most strongly associated with CYHR1. Immunoblots found the abundance of intact OSMRβ and CYHR1 significantly differed between good and poor responders. Thus, two measurable biomarkers of the response to erythropoietic-stimulating agents are present in the serum of treated patients.
doi:10.1038/ki.2010.468
PMCID: PMC4024449  PMID: 21150872
anemia; biomarker; erythropoietic; hemodialysis; peptidomics

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