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2.  An immunostimulatory dual-functional nanocarrier that improves cancer immunochemotherapy 
Nature Communications  2016;0:13443.
Immunochemotherapy combines a chemotherapeutic agent with an immune-modulating agent and represents an attractive approach to improve cancer therapy. However, the success of immunochemotherapy is hampered by the lack of a strategy to effectively co-deliver the two therapeutics to the tumours. Here we report the development of a dual-functional, immunostimulatory nanomicellar carrier that is based on a prodrug conjugate of PEG with NLG919, an indoleamine 2,3-dioxygenase (IDO) inhibitor currently used for reversing tumour immune suppression. An Fmoc group, an effective drug-interactive motif, is also introduced into the carrier to improve the drug loading capacity and formulation stability. We show that PEG2k-Fmoc-NLG alone is effective in enhancing T-cell immune responses and exhibits significant antitumour activity in vivo. More importantly, systemic delivery of paclitaxel (PTX) using the PEG2k-Fmoc-NLG nanocarrier leads to a significantly improved antitumour response in both breast cancer and melanoma mouse models.
The use of immunostimulatory agents to enhance the efficacy of chemotherapy is a promising strategy in cancer therapy. Here, the authors report on a micellar nanoparticle that can effectively co-deliver chemo- and immunotherapeutics, resulting in an improved in vivo antitumour response.
doi:10.1038/ncomms13443
PMCID: PMC5103075  PMID: 27819653
3.  Effective co-delivery of doxorubicin and dasatinib using a PEG-Fmoc nanocarrier for combination cancer chemotherapy 
Biomaterials  2015;67:104-114.
A simple PEGylated peptidic nanocarrier, PEG5000-lysyl-(α-Fmoc-ε-Cbz-lysine)2 (PLFCL), was developed for effective co-delivery of doxorubicin (DOX) and dasatinib (DAS) for combination chemotherapy. Significant synergy of DOX and DAS in inhibition of cancer cell proliferation was demonstrated in various types of cancer cells, including breast, prostate, and colon cancers. Co-encapsulation of the two agents was facilitated by incorporation of 9-Fluorenylmethoxycarbonyl (Fmoc) and carboxybenzyl (Cbz) groups into a nanocarrier for effective carrier-drug interactions. Spherical nanomicelles with a small size of ~30 nm were self-assembled by PLFCL. Strong carrier/drug intermolecular π-π stacking was demonstrated in fluorescence quenching and UV absorption. Fluorescence study showed more effective accumulation of DOX in nuclei of cancer cells following treatment with DOX&DAS/PLFCL in comparison with cells treated with DOX/PLFCL. DOX&DAS/PLFCL micelles were also more effective than other treatments in inhibiting the proliferation and migration of cultured cancer cells. Finally, a superior anti-tumor activity was demonstrated with DOX&DAS/PLFCL. A tumor growth inhibition rate of 95% was achieved at a respective dose of 5 mg/kg for DOX and DAS in a murine breast cancer model. Our nanocarrier may represent a simple and effective system that could facilitate clinical translation of this promising multi-agent regimen in combination chemotherapy.
doi:10.1016/j.biomaterials.2015.07.027
PMCID: PMC4550547  PMID: 26210177
combination chemotherapy; micelle; 9-Fluorenylmethoxycarbonyl; carrier-drug interaction; doxorubicin; dasatinib
4.  Integrative analyses of human reprogramming reveal dynamic nature of induced pluripotency 
Cell  2015;162(2):412-424.
Summary
Induced pluripotency is a promising avenue for disease modeling and therapy, but the molecular principles underlying this process, particularly in human cells, remain poorly understood due to donor-to-donor variability and intercellular heterogeneity. Here we constructed and characterized a clonal, inducible human reprogramming system that provides a reliable source of cells at any stage of the process. This system enabled integrative transcriptional and epigenomic analysis across the human reprogramming timeline at high resolution. We observed distinct waves of gene network activation, including the ordered reactivation of broad developmental regulators followed by early embryonic patterning genes and culminating in the emergence of a signature reminiscent of pre-implantation stages. Moreover, complementary functional analyses allowed us to identify and validate novel regulators of the reprogramming process. Altogether, this study sheds light on the molecular underpinnings of induced pluripotency in human cells and provides a robust cell platform for further studies.
doi:10.1016/j.cell.2015.06.016
PMCID: PMC4511597  PMID: 26186193
5.  Iron and Noncontrast Magnetic Resonance T2* as a Marker of Intraplaque Iron in Human Atherosclerosis 
Journal of vascular surgery  2014;61(6):1556-1564.
Objective
Iron has been implicated in atherogenesis and plaque destabilization, while less is known regarding iron-related proteins in this disease. We compared ex vivo quantities to in vivo vessel wall T2*, which is a noncontrast magnetic resonance relaxation time that quantitatively shortens with increased tissue iron content. We also tested the hypothesis that carotid atherosclerosis patients have abnormal T2* times vs. controls that would help support a role for iron in human atherosclerosis.
Methods and Results
46 patients undergoing carotid endarterectomy and 14 subjects without carotid disease were prospectively enrolled to undergo carotid MRI. Ex vivo measurements were performed on explanted plaque and 17 mammary artery samples. Plaques vs. normal arteries had higher levels of ferritin (median = 7.3 [IQR=4 – 13.8] vs. 1.0 [0.6 – 1.3] ng/mg, P < .001) and oxidized low-density lipoprotein (0.17 [0.12 – 0.30] vs. 0.01 [0.003 – 0.03] ng/mg, P < .001) as well as hepcidin (8.7 [4.6 – 12.4] vs. 2.6 [1.3 – 7.0] ng/mL, P = .03); serum hepcidin levels did not distinguish atherosclerosis patients from controls (40.6 [18.8 – 88.6] vs. 33.9 [17.6 – 55.2], P = 0.42). Shorter in vivo T2* paralleled larger plaque volume (ρ = −.44, p = 0.01), and diseased arteries had shorter T2* values compared to controls (17.7 ± 4.3 vs. 23.0 ± 2.4 ms, P < .001).
Conclusions
Diseased arteries have greater levels of iron-related proteins ex vivo and shorter T2* times in vivo. Further studies should help define T2*'s role as a biomarker of iron and atherosclerosis.
doi:10.1016/j.jvs.2014.02.006
PMCID: PMC4175307  PMID: 24674272
6.  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
7.  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
8.  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
9.  MADS-Box Genes and Gibberellins Regulate Bolting in Lettuce (Lactuca sativa L.) 
Bolting in lettuce is promoted by high temperature and bolting resistance is of great economic importance for lettuce production. But how bolting is regulated at the molecular level remains elusive. Here, a bolting resistant line S24 and a bolting sensitive line S39 were selected for morphological, physiological, transcriptomic and proteomic comparisons. A total of 12204 genes were differentially expressed in S39 vs. S24. Line S39 was featured with larger leaves, higher levels of chlorophyll, soluble sugar, anthocyanin and auxin, consistent with its up-regulation of genes implicated in photosynthesis, oxidation-reduction and auxin actions. Proteomic analysis identified 30 differentially accumulated proteins in lines S39 and S24 upon heat treatment, and 19 out of the 30 genes showed differential expression in the RNA-Seq data. Exogenous gibberellins (GA) treatment promoted bolting in both S39 and S24, while 12 flowering promoting MADS-box genes were specifically induced in line S39, suggesting that although GA regulates bolting in lettuce, it may be the MADS-box genes, not GA, that plays a major role in differing the bolting resistance between these two lettuce lines.
doi:10.3389/fpls.2016.01889
PMCID: PMC5159435  PMID: 28018414
lettuce; bolting; flowering integrators; RNA-Seq; proteomics
10.  Design and Synthesis of a Mitochondria-Targeted Mimic of Glutathione Peroxidase, MitoEbselen-2, as a Radiation Mitigator 
ACS Medicinal Chemistry Letters  2014;5(12):1304-1307.
Ionizing radiation (IR) triggers mitochondrial overproduction of H2O2 and accumulation of lipid hydroperoxides leading to the induction of apoptotic and necroptotic cell death pathways. Given the high catalytic efficiency of the seleno-enzyme glutathione peroxidase (Gpx) toward reduction of lipid hydroperoxides and H2O2, we tested the potential of mitochondria-targeted derivatives of ebselen to mitigate the deleterious effects of IR. We report that 2-[[2-[4-(3-oxo-1,2-benzoselenazol-2-yl)phenyl]acetyl]amino]ethyl-triphenyl-phosphonium chloride (MitoPeroxidase 2) was effective in reducing lipid hydroperoxides, preventing apoptotic cell death, and, when administered 24 h postirradiation, increased the survival of mice exposed to whole body γ-irradiation.
doi:10.1021/ml5003635
PMCID: PMC4266336  PMID: 25530831
Ebselen; mitochondria; H2O2; radiation; mitigators; apoptosis
11.  Design and Synthesis of a Mitochondria-Targeted Mimic of Glutathione Peroxidase, MitoEbselen-2, as a Radiation Mitigator 
ACS Medicinal Chemistry Letters  2014;5(12):1304-1307.
Ionizing radiation (IR) triggers mitochondrial overproduction of H2O2 and accumulation of lipid hydroperoxides leading to the induction of apoptotic and necroptotic cell death pathways. Given the high catalytic efficiency of the seleno-enzyme glutathione peroxidase (Gpx) toward reduction of lipid hydroperoxides and H2O2, we tested the potential of mitochondria-targeted derivatives of ebselen to mitigate the deleterious effects of IR. We report that 2-[[2-[4-(3-oxo-1,2-benzoselenazol-2-yl)phenyl]acetyl]amino]ethyl-triphenyl-phosphonium chloride (MitoPeroxidase 2) was effective in reducing lipid hydroperoxides, preventing apoptotic cell death, and, when administered 24 h postirradiation, increased the survival of mice exposed to whole body γ-irradiation.
doi:10.1021/ml5003635
PMCID: PMC4266336  PMID: 25530831
Ebselen; mitochondria; H2O2; radiation; mitigators; apoptosis
12.  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
13.  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
14.  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
15.  HANABA TARANU (HAN) Bridges Meristem and Organ Primordia Boundaries through PINHEAD, JAGGED, BLADE-ON-PETIOLE2 and CYTOKININ OXIDASE 3 during Flower Development in Arabidopsis  
PLoS Genetics  2015;11(9):e1005479.
Shoot organ primordia are initiated from the shoot apical meristem and develop into leaves during the vegetative stage, and into flowers during the reproductive phase. Between the meristem and the newly formed organ primordia, a boundary with specialized cells is formed that separates meristematic activity from determinate organ growth. Despite interactions that have been found between boundary regulators with genes controlling meristem maintenance or primordial development, most boundary studies were performed during embryogenesis or vegetative growth, hence little is known about whether and how boundaries communicate with meristem and organ primordia during the reproductive stage. We combined genetic, molecular and biochemical tools to explore interactions between the boundary gene HANABA TARANU (HAN) and two meristem regulators BREVIPEDICELLUS (BP) and PINHEAD (PNH), and three primordia-specific genes PETAL LOSS (PTL), JAGGED (JAG) and BLADE-ON-PETIOLE (BOP) during flower development. We demonstrated the key role of HAN in determining petal number, as part of a set of complex genetic interactions. HAN and PNH transcriptionally promote each other, and biochemically interact to regulate meristem organization. HAN physically interacts with JAG, and directly stimulates the expression of JAG and BOP2 to regulate floral organ development. Further, HAN directly binds to the promoter and intron of CYTOKININ OXIDASE 3 (CKX3) to modulate cytokinin homeostasis in the boundary. Our data suggest that boundary-expressing HAN communicates with the meristem through the PNH, regulates floral organ development via JAG and BOP2, and maintains boundary morphology through CKX3 during flower development in Arabidopsis.
Author Summary
The shoot apical meristem is the stem cell pool in plants that gives rise to all above-ground organs including leaves, flowers and fruits. Between the meristem and the newly formed organ primordia, a boundary with specialized cells is formed to separate them. Boundary genes are specifically expressed in boundaries and function in boundary formation and maintenance. Previous studies showed that boundary genes interact with meristem regulators and primordia genes during embryogenesis or leaf development. But whether and how boundaries communicate with meristem and organ primordia during flower development remains largely unknown. Here we combined genetic, molecular and biochemical tools to explore interactions between the boundary gene HANABA TARANU (HAN) and two meristem regulators BREVIPEDICELLUS (BP) and PINHEAD (PNH), and three primordia-specific genes PETAL LOSS (PTL), JAGGED (JAG) and BLADE-ON-PETIOLE (BOP) during flower development. We showed that boundary-expressing HAN communicates with the meristem through PNH, regulates floral organ development via JAG and BOP2, and maintains boundary morphology through CYTOKININ OXIDASE 3 (CKX3)-mediated cytokinin homeostasis. Thus, our findings shed light on the “bridge” role of boundaries between meristem and organ primordia during flower development in Arabidopsis.
doi:10.1371/journal.pgen.1005479
PMCID: PMC4577084  PMID: 26390296
16.  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
17.  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.
18.  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
19.  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
20.  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
21.  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
22.  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
23.  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
24.  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
25.  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

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