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1.  Active Targeting Using HER-2-affibody-conjugated Nanoparticles Enabled Sensitive and Specific Imaging of Orthotopic HER-2 Positive Ovarian Tumors 
Despite advances in cancer diagnosis and treatment, ovarian cancer remains one of the most fatal cancer types. The development of targeted nanoparticle imaging probes and therapeutics offers promising approaches for early detection and effective treatment of ovarian cancer. In this study, we have developed HER-2 targeted magnetic iron oxide nanoparticles (IONPs) by conjugating a high affinity and small size HER-2 affibody that is labeled with a unique near infrared dye (NIR-830) to the nanoparticles. Using a clinically relevant orthotopic human ovarian tumor xenograft model, we have shown that HER-2 targeted IONPs are selectively delivered into both primary and disseminated ovarian tumors, enabling non-invasive optical and MR imaging of the tumors as small as 1 mm in the peritoneal cavity. We have determined that HER-2 targeted delivery of the IONPs is essential for specific and sensitive imaging of the HER-2 positive tumor since we are unable to detect the imaging signal in the tumors following systemic delivery of non-targeted IONPs into the mice bearing HER-2 positive SKOV3 tumors. Furthermore, imaging signals and the IONPs are not detected in HER-2 low expressing OVCAR3 tumors after systemic delivery of HER-2 targeted-IONPs. Since HER-2 is expressed in a high percentage of ovarian cancers, the HER-2 targeted dual imaging modality IONPs have potential for the development of novel targeted imaging and therapeutic nanoparticles for ovarian cancer detection, targeted drug delivery, and image-guided therapy and surgery.
doi:10.1002/smll.201301593
PMCID: PMC3946402  PMID: 24038985
HER-2 targeted nanoparticles; HER-2 affibody; NIR-830 dye; orthotopic human ovarian tumor xenograft model
2.  Making the lifetime connection between brain and machine for restoring and enhancing function 
Progress in brain research  2011;194:1-25.
A reliable neural interface that lasts a lifetime will lead to the development of neural prosthetic devices as well as the possibility that brain function can be enhanced. Our data demonstrate that a reliable neural interface is best achieved when the surrounding neuropil grows into the electrode tip where it is held securely, allowing myelinated axons to be recorded using implanted amplifiers. Stable single and multiunits were recorded from three implanted subjects and classified according to amplitudes and firing rates. In one paralyzed and mute subject implanted for over 5 years with a double electrode in the speech motor cortex, the single units allowed recognition of over half the 39 English language phonemes detected using a variety of decoding methods. These single units were used by the subject in a speech task where vowel phonemes were recognized and fed back to the subject using audio output. Weeks of training resulted in an 80% success rate in producing four vowels in an adaptation of the classic center-out task used in motor control studies. The importance of using single units was shown in a different task using pure tones that the same subject heard and then sung or hummed in his head. Feedback was associated with smoothly coordinated unit firings. The plasticity of the unit firings was demonstrated over several sessions first without, and then with, feedback. These data suggest that units can be reliably recorded over years, that there is an inverse relationship between single unit firing rate and amplitude, that pattern recognition decoding paradigms can allow phoneme recognition, that single units appear more important than multiunits when precision is important, and that units are plastic in their functional relationships. These characteristics of a reliable neural interface are essential for the development of neural prostheses and also for the future enhancement of human brain function.
doi:10.1016/B978-0-444-53815-4.00020-0
PMCID: PMC4305334  PMID: 21867791
brain computer interfacing; brain machine interfacing; neurotrophic electrode; long-term human recording; speech prosthesis; single unit recording; multi-unit recording; local field potentials
3.  Facile non-hydrothermal synthesis of oligosaccharides coated sub-5 nm magnetic iron oxide nanoparticles with dual MRI contrast enhancement effect 
Ultrafine sub-5 nm magnetic iron oxide nanoparticles coated with oligosaccharides (SIO) with dual T1-T2 weighted contrast enhancing effect and fast clearance has been developed as magnetic resonance imaging (MRI) contrast agent. Excellent water solubility, biocompatibility and high stability of such sub-5 nm SIO nanoparticles were achieved by using the “in-situ polymerization” coating method, which enables glucose forming oligosaccharides directly on the surface of hydrophobic iron oxide nanocrystals. Reported ultrafine SIO nanoparticles exhibit a longitudinal relaxivity (r1) of 4.1 mM−1s−1 and a r1/r2 ratio of 0.25 at 3 T (clinical field strength), rendering improved T1 or “brighter” contrast enhancement in T1-weighted MRI in addition to typical T2 or “darkening” contrast of conventional iron oxide nanoparticles. Such dual contrast effect can be demonstrated in liver imaging with T2 “darkening” contrast in the liver parenchyma but T1 “bright” contrast in the hepatic vasculature. More importantly, this new class of ultrafine sub-5 nm iron oxide nanoparticles showed much faster body clearance than those with larger sizes, promising better safety for clinical applications.
doi:10.1039/C4TB00811A
PMCID: PMC4147377  PMID: 25181490
4.  Theranostic Nanoparticles Carrying Doxorubicin Attenuate Targeting Ligand Specific Antibody Responses Following Systemic Delivery 
Theranostics  2015;5(1):43-61.
Understanding the effects of immune responses on targeted delivery of nanoparticles is important for clinical translations of new cancer imaging and therapeutic nanoparticles. In this study, we found that repeated administrations of magnetic iron oxide nanoparticles (IONPs) conjugated with mouse or human derived targeting ligands induced high levels of ligand specific antibody responses in normal and tumor bearing mice while injections of unconjugated mouse ligands were weakly immunogenic and induced a very low level of antibody response in mice. Mice that received intravenous injections of targeted and polyethylene glycol (PEG)-coated IONPs further increased the ligand specific antibody production due to differential uptake of PEG-coated nanoparticles by macrophages and dendritic cells. However, the production of ligand specific antibodies was markedly inhibited following systemic delivery of theranostic nanoparticles carrying a chemotherapy drug, doxorubicin. Targeted imaging and histological analysis revealed that lack of the ligand specific antibodies led to an increase in intratumoral delivery of targeted nanoparticles. Results of this study support the potential of further development of targeted theranostic nanoparticles for the treatment of human cancers.
doi:10.7150/thno.10350
PMCID: PMC4265747  PMID: 25553097
Targeting ligands; nanoparticles; antibody; immune response; tumor imaging; nanoparticle delivery.
5.  Healing time of incision infection after hepatobiliary surgery treated by needle-free incision suture closure 
World Journal of Gastroenterology : WJG  2014;20(42):15815-15819.
AIM: To compare the effectiveness of needle-free incision suture closure with butterfly tape and traditional secondary suturing techniques in treating incision infection.
METHODS: Two hundred and twenty-three patients with incision infection following hepatobiliary surgery at a tertiary hospital were randomly divided into three groups: 90 patients were closed by needle-free incision suture closure, which gradually closed the incision wound when drainage from incision infection was visibly decreased and healthy granulation tissues had grown; 79 patients were closed by butterfly bandage; another 54 patients were closed by traditional secondary suturing technique. Healing time of incision infection was calculated from the beginning of dressing change to the healing of the incision.
RESULTS: Healing time in the needle-free incision suture closure group (24.2 ± 7.2 d) was significantly shorter than that in the butterfly bandage group (33.3 ± 11.2 d) and the traditional secondary suturing group (36.2 ± 15.3 d) (P < 0.05). Healing time in the butterfly bandage group appeared to be slightly shorter than that in the secondary suture group, but the difference was not statistically significant (P > 0.05).
CONCLUSION: Needle-free incision suture closure could gradually close the infection wound at the same time of drainage and dressing change, thereby shortening the healing time.
doi:10.3748/wjg.v20.i42.15815
PMCID: PMC4229548  PMID: 25400467
Incision infection; Needle-free incision suture closure; Secondary suture; Drainage; Wound healing; Hepatobiliary surgery
6.  Engineering geminivirus resistance in Jatropha curcus 
Biotechnology for Biofuels  2014;7(1):149.
Background
Jatropha curcus is a good candidate plant for biodiesel production in tropical and subtropical regions. However, J. curcus is susceptible to the geminivirus Indian cassava mosaic virus (ICMV), and frequent viral disease outbreaks severely limit productivity. Therefore the development of J. curcus to carry on durable virus resistance remains crucial and poses a major biotechnological challenge.
Results
We generated transgenic J. curcus plants expressing a hairpin, double-stranded (ds) RNA with sequences homologous to five key genes of ICMV-Dha strain DNA-A, which silences sequence-related viral genes thereby conferring ICMV resistance. Two rounds of virus inoculation were conducted via vacuum infiltration of ICMV-Dha. The durability and heritability of resistance conferred by the dsRNA was further tested to ascertain that T1 progeny transgenic plants were resistant to the ICMV-SG strain, which shared 94.5% nucleotides identity with the ICMV-Dha strain. Quantitative PCR analysis showed that resistant transgenic lines had no detectable virus.
Conclusions
In this study we developed transgenic J. curcus plants to include a resistance to prevailing geminiviruses in Asia. These virus-resistant transgenic J. curcus plants can be used in various Jatropha breeding programs.
Electronic supplementary material
The online version of this article (doi:10.1186/s13068-014-0149-z) contains supplementary material, which is available to authorized users.
doi:10.1186/s13068-014-0149-z
PMCID: PMC4210599  PMID: 25352912
Biodiesel; Indian cassava mosaic virus; Jatropha curcus; Virus resistance; Transgenic
7.  Detection of “oncometabolite” 2-hydroxyglutarate by magnetic resonance analysis as a biomarker of IDH1/2 mutations in glioma 
Somatic mutations in isocitrate dehydrogenase (IDH)1 and 2 have been identified in a subset of gliomas, rendering these tumors with elevated levels of “oncometabolite,” D-2-hydroxyglutarate (2HG). Herein, we report that 2HG can be precisely detected by magnetic resonance (MR) in human glioma specimens and used as a reliable biomarker to identify this subset of tumors. Specifically, we developed a two-dimensional correlation spectroscopy resonance method to reveal the distinctive cross-peak pattern of 2HG in the complex metabolite nuclear MR spectra of brain tumor tissues. This study demonstrates the feasibility, specificity, and selectivity of using MR detection and quantification of 2HG for the diagnosis and classification of IDH1/2 mutation-positive brain tumors. It further opens up the possibility of developing analogous non-invasive MR-based imaging and spectroscopy studies directly in humans in the neuro-oncology clinic.
doi:10.1007/s00109-012-0888-x
PMCID: PMC4147374  PMID: 22426639
Cancer; 2-Hydroxyglutarate; Isocitrate dehydrogenase; Nuclear magnetic resonance; Biomarker
8.  Development of Receptor Targeted Magnetic Iron Oxide Nanoparticles for Efficient Drug Delivery and Tumor Imaging 
The development of multifunctional nanoparticles that have dual capabilities of tumor imaging and delivering therapeutic agents into tumor cells holds great promises for novel approaches for tumor imaging and therapy. We have engineered urokinase plasminogen activator receptor (uPAR) targeted biodegradable nanoparticles using a size uniform and amphiphilic polymer-coated magnetic iron oxide (IO) nanoparticle conjugated with the amino-terminal fragment (ATF) of urokinase plasminogen activator (uPA), which is a high affinity natural ligand for uPAR. We further developed methods to encapsulate hydrophobic chemotherapeutic drugs into the polymer layer on the IO nanoparticles, making these targeted magnetic resonance imaging (MRI) sensitive nanoparticles drug delivery vehicles. Using a fluorescent drug doxorubicin (Dox) as a model system, we showed that this hydrophobic drug can be efficiently encapsulated into the uPAR-targeted IO nanoparticles. This class of Dox-loaded nanoparticles has a compact size and is stable in pH 7.4 buffer. However, encapsulated Doxcan be released from the nanoparticles at pH 4.0 to 5.0 within 2 hrs. In comparison with the effect of equivalent dosage of free drug or non-targeted IO-Dox nanoparticles, uPAR-targeted IO-Dox nanoparticles deliver higher levels of Dox into breast cancer cells and produce a stronger inhibitory effect on tumor cell growth. Importantly, Dox-loaded IO nanoparticles maintain their T2 MRI contrast effect after being internalized into the tumor cells due to their significant susceptibility effect in the cells, indicating that this drug delivery nanoparticle has the potential to be used as targeted therapeutic imaging probes for monitoring the drug delivery using MRI.
doi:10.1166/jbn.2008.007
PMCID: PMC4139059  PMID: 25152701
Magnetic Iron Oxide Nanoparticles; uPAR; Targeted Nanoparticle; Breast Cancer; Drug Delivery Nanoparticle; Doxorubicin
9.  Prognostic and clinicopathological significance of microRNA-21 overexpression in breast cancer: a meta-analysis 
Recent studies have highlighted the role of microRNA-21 (miR-21) as a prognostic biomarker of breast cancer. However, controversy still remains. The present study aimed to summarize available evidences and obtain a more precise estimation of a prognostic role of miR-21 in breast cancer patients. All eligible studies were searched from PubMed and EMBASE through multiple search strategies. Data were extracted from studies comparing survival in breast cancer patients having higher miR-21 expression with those having lower expression. A meta-analysis was performed to clarify prognostic role of miR-21 in patients with breast cancer. Subgroup analysis was also performed according to patients’ ethnicity. A total of 6 eligible articles comprising 951 cases were selected for this meta-analysis. The combined hazard ratios (HRs) and 95% confidence intervals (95% CIs) for overall survival (OS) were 2.11 (1.09-4.08) and for disease free survival (DFS) was 1.6 (1.30-1.96). Subgroup analysis indicated high miR-21 expression was significantly associated with worse OS in Asian patients (HR = 4.39, 95% CI: 2.47-7.80) but not in non-Asian patients (HR = 1.18, 95% CI: 0.81-1.70). Sensitivity analysis revealed results of this meta-analysis were robust. Odds ratios (ORs) showed that miR-21 expression was closely associated with estrogen receptor (ER), progesterone receptor (PR), lymph node metastasis, histological grade, Her2/neu. The pooled ORs and 95% CIs were 0.53 (0.35-0.80), 0.49 (0.32-0.74), 2.32 (1.54-3.50), 2.44 (1.58-3.75), 4.29 (2.34-7.85), respectively. Our results indicated that elevated miR-21 expression could potentially predict poor survival in patients with breast cancer.
PMCID: PMC4203174  PMID: 25337203
MicroRNA-21; breast cancer; prognosis; biomarker; meta-analysis
10.  HRMAS 1H-NMR measured changes of the metabolite profile as mesenchymal stem cells differentiate to targeted fat cells in vitro: implications for non-invasive monitoring of stem cell differentiation in vivo 
Mesenchymal stemcells (MSCs) have shown a great potential for clinical applications in regenerative medicine. However, it remains challenging to follow the transplanted cell grafts in vivo. Nuclear magnetic resonance spectroscopy (NMR or MRS) is capable of determining and quantifying the cellular metabolites in tissue and organs non-invasively, therefore it is an attractive method for monitoring and evaluating the differentiation and functions of transplanted stem cells in vivo. In this study, metabolic changes of MSCs undergoing adipogenic differentiation to targeted fat cells were investigated in vitro, using solid-state high-resolution magic angle spinning 1H nuclear magnetic resonance spectroscopy. Quantification of metabolite concentrations before and after differentiation of MSCs showed decreased levels of intracellular metabolites, including choline, creatine, glutamate and myo-inositol, and a substantially increased level of fatty acids, when mesenchymal stem cells were differentiated preferentially to fat cells. Intracellular creatine, myo-inositol and choline reduced from 10.4 ± 0.72, 16.2 ± 1.2 and 8.22 ± 0.51 mm to 3.27 ± 0.34, 6.1 ± 0.46 and 3.11 ± 0.32 mm, respectively, while fatty acids increased from 32.6 ± 1.5 to 91.2 ± 3.2 mm after undergoing 3 weeks of differentiation. The increase of the fatty acid concentration measured by NMR is confirmed by the observation of 80% fat cells in differentiated cells by cell counting assay, suggesting resonances from fatty acids may be used as metabolite markers for monitoring MSC differentiation to fat cells in vivo, using the magnetic resonance spectroscopic technique readily available on MRI scanners.
doi:10.1002/term.120
PMCID: PMC4112179  PMID: 18932127
stem cell; metabolite; adipogenic differentiation; magnetic resonance; imaging; spectroscopy
11.  Casein-coated Iron Oxide Nanoparticles for High MRI Contrast Enhancement and Efficient Cell Targeting 
ACS applied materials & interfaces  2013;5(11):4632-4639.
Surface properties, as well as inherent physicochemical properties, of the engineered nanomaterials play important roles in their interactions with the biological systems, which eventually affect their efficiency in diagnostic and therapeutic applications. Here we report a new class MRI contrast agent based on milk casein protein coated iron oxide nanoparticles (CNIOs) with a core size of 15 nm and hydrodynamic diameter ~30 nm. These CNIOs exhibited excellent water-solubility, colloidal stability, and biocompatibility. Importantly, CNIOs exhibited prominent T2 enhancing capability with a transverse relaxivity r2 of 273 mM−1s−1 at 3 Tesla. The transverse relaxivity is ~2.5-fold higher than that of iron oxide nanoparticles with the same core but an amphiphilic polymer coating. CNIOs showed pH-responsive properties, formed loose and soluble aggregates near the pI (pH~4.0). The aggregates could be dissociated reversibly when the solution pH was adjusted away from the pI. The transverse relaxation property and MRI contrast enhancing effect of CNIOs remained unchanged in the pH range of 2.0 to 8.0. Further functionalization of CNIOs can be achieved via surface modification of the protein coating. Bio-affinitive ligands, such as a single chain fragment from the antibody of epidermal growth factor receptor (ScFvEGFR), could be readily conjugated onto the protein coating, enabling specific targeting to MDA-MB-231 breast cancer cells over-expressing EGFR. T2-weighted MRI of mice intravenously administered with CNIOs demonstrated strong contrast enhancement in the liver and spleen. These favorable properties suggest CNIOs as a class of biomarker targeted magnetic nanoparticles for MRI contrast enhancement and related biomedical applications.
doi:10.1021/am400713j
PMCID: PMC3699787  PMID: 23633522
iron; oxide; nanoparticles; magnetic resonance; imaging; casein; contrast agent; targeting
12.  A novel long non-coding RNA FOXCUT and mRNA FOXC1 pair promote progression and predict poor prognosis in esophageal squamous cell carcinoma 
Accumulating evidences demonstrated that many long non-coding RNAs (lncRNAs) can cooperate with the adjacent coding genes, forming into “lncRNA-mRNA gene pairs” in multiple biological cellular processes. Here, we showed that a novel long non-coding RNA FOXCUT (FOXC1 promoter upstream transcript) and its neighboring gene FOXC1 played a similar important role in the oncogenesis and progression of esophageal squamous cell carcinoma (ESCC). In this study, the expression of FOXCUT/FOXC1 was measured in 82 ESCC tissues and adjacent noncancerous tissues by real-time quantitative PCR (qPCR). The prognostic significance of the lncRNA-mRNA gene pair was evaluated using Kaplan-Meier survival analysis and log-rank test. Cell biological experiments were performed in ESCC cell lines to explore their functions in tumor progression. Notably elevated FOXCUT and FOXC1 expression levels were observed in cancerous tissues compared to adjacent noncancerous tissues (86.6% and 84.1%, respectively; P < 0.01), showing strong correlations with poor differentiation, advanced lymph node classification and metastasis (P < 0.05). Moreover, patients with upregulated FOXCUT or FOXC1 experienced a significantly worse prognosis than those with downregulated FOXCUT or FOXC1 (P < 0.001 and P = 0.014, respectively). In addition, the expression of FOXCUT was positively correlated with expression of FOXC1 in ESCC specimens. And the expression of FOXC1 was also decreased as the FOXCUT expression was silenced by siRNA. Assays in vitro demonstrated that knockdown of either FOXCUT or FOXC1 remarkably inhibited cell proliferation, colony formation, migration, invasion in ESCC cells. In conclusion, FOXCUT may be functionally involved in the tumor progression and survival of ESCC patients, at least in part, by modulating FOXC1. FOXCUT and FOXC1 may function as a lncRNA-mRNA gene pair, which may represent a potential prognostic biomarker and therapeutic target for ESCC patients.
PMCID: PMC4097289  PMID: 25031703
ESCC; lncRNA; FOXC1; FOXCUT; progression; prognosis
13.  Theranostic Nanoparticles with Controlled Release of Gemcitabine for Targeted Therapy and MRI of Pancreatic Cancer 
ACS nano  2013;7(3):2078-2089.
The tumor stroma in human cancers significantly limits the delivery of therapeutic agents into cancer cells. To develop an effective therapeutic approach overcoming the physical barrier of the stroma, we engineered urokinase plasminogen activator receptor (uPAR)-targeted magnetic iron oxide nanoparticles (IONPs) carrying gemcitabine (Gem) as a chemotherapy drug for targeted delivery into uPAR-expressing tumor and stromal cells. The uPAR-targeted nanoparticle construct, ATF-IONP-Gem, was prepared by conjugating IONPs with the amino-terminal fragment (ATF) peptide of the receptor-binding domain of uPA, a natural ligand of uPAR, and Gem via a lysosomally cleavable tetrapeptide linker. These theranostic nanoparticles enable intracellular release of Gem following receptor-mediated endocytosis of ATF-IONP-Gem into tumor cells, and also allow in vivo magnetic resonance imaging (MRI) of tumors. Our results demonstrated the pH- and lysosomal enzyme-dependent release of gemcitabine, preventing the drug from enzymatic degradation. Systemic administrations of ATF-IONP-Gem significantly inhibited the growth of orthotopic human pancreatic cancer xenografts in nude mice. With MRI contrast enhancement by IONPs, we detected the presence of IONPs in the residual tumor lesions following the treatment, suggesting the possibility of monitoring drug delivery and assessing drug resistant tumors by MRI. The theranostic ATF-IONP-Gem nanoparticle has great potential for the development of targeted therapeutic and imaging approaches that are capable of overcoming the tumor stromal barrier, thus enhancing the therapeutic effect of nanoparticle drugs on pancreatic cancers.
doi:10.1021/nn3043463
PMCID: PMC3609912  PMID: 23402593
targeted cancer therapy; theranostic nanoparticle; uPAR; pancreatic cancer; gemcitabine; controlled drug release; magnetic resonance imaging; drug delivery
14.  Gene silencing of Sugar-dependent 1 (JcSDP1), encoding a patatin-domain triacylglycerol lipase, enhances seed oil accumulation in Jatropha curcas 
Background
Triacylglycerols (TAGs) are the most abundant form of storage oil in plants. They consist of three fatty acid chains (usually C16 or C18) covalently linked to glycerol. SDP1 is a specific lipase for the first step of TAG catabolism in Arabidopsis seeds. Arabidopsis mutants deficient in SDP1 accumulate high levels of oils, probably due to blockage in TAG degradation. We applied this knowledge from the model plant, Arabidopsis thaliana, to engineer increased seed oil content in the biodiesel plant Jatropha curcas using RNA interference (RNAi) technology.
Results
As Jatropha is a biodiesel crop, any significant increase in its seed oil content would be an important agronomic trait. Using A. thaliana as a model plant, we found that a deficiency of SDP1 led to higher TAG accumulation and a larger number of oil bodies in seeds compared with wild type (Columbia-0; Col-0). We cloned Jatropha JcSDP1, and verified its function by complementation of the Arabidopsis sdp1-5 mutant. Taking advantage of the observation with Arabidopsis, we used RNAi technology to generate JcSDP1 deficiency in transgenic Jatropha. We found that Jatropha JcSDP1-RNAi plants accumulated 13 to 30% higher total seed storage lipid, along with a 7% compensatory decrease in protein content, compared with control (CK; 35S:GFP) plants. Free fatty acid (FFA) content in seeds was reduced from 27% in control plants to 8.5% in JcSDP1-RNAi plants.
Conclusion
Here, we showed that SDP1 deficiency enhances seed oil accumulation in Arabidopsis. Based on this result, we generated SDP1-deficient transgenic Jatropha plants using by RNAi technology with a native JcSDP1 promoter to silence endogenous JcSDP1 expression. Seeds of Jatropha JcSDP1-RNAi plants accumulated up to 30% higher total lipid and had reduced FFA content compared with control (CK; 35S:GFP) plants. Our strategy of improving an important agronomic trait of Jatropha can be extended to other oil crops to yield higher seed oil.
doi:10.1186/1754-6834-7-36
PMCID: PMC4016141  PMID: 24606605
Inducible maker-free JcSDP1-RNAi; Jatropha; sdp1-5; Triacylglycerols (TAGs)
15.  A two years longitudinal study of a transgenic Huntington disease monkey 
BMC Neuroscience  2014;15:36.
Background
A two-year longitudinal study composed of morphometric MRI measures and cognitive behavioral evaluation was performed on a transgenic Huntington’s disease (HD) monkey. rHD1, a transgenic HD monkey expressing exon 1 of the human gene encoding huntingtin (HTT) with 29 CAG repeats regulated by a human polyubiquitin C promoter was used together with four age-matched wild-type control monkeys. This is the first study on a primate model of human HD based on longitudinal clinical measurements.
Results
Changes in striatal and hippocampal volumes in rHD1 were observed with progressive impairment in motor functions and cognitive decline, including deficits in learning stimulus-reward associations, recognition memory and spatial memory. The results demonstrate a progressive cognitive decline and morphometric changes in the striatum and hippocampus in a transgenic HD monkey.
Conclusions
This is the first study on a primate model of human HD based on longitudinal clinical measurements. While this study is based a single HD monkey, an ongoing longitudinal study with additional HD monkeys will be important for the confirmation of our findings. A nonhuman primate model of HD could complement other animal models of HD to better understand the pathogenesis of HD and future development of diagnostics and therapeutics through longitudinal assessment.
doi:10.1186/1471-2202-15-36
PMCID: PMC4015530  PMID: 24581271
16.  Longitudinal Monitoring of Stem Cell Grafts In Vivo Using Magnetic Resonance Imaging with Inducible Maga as a Genetic Reporter 
Theranostics  2014;4(10):972-989.
Purpose: The ability to longitudinally monitor cell grafts and assess their condition is critical for the clinical translation of stem cell therapy in regenerative medicine. Developing an inducible genetic magnetic resonance imaging (MRI) reporter will enable non-invasive and longitudinal monitoring of stem cell grafts in vivo. Methods: MagA, a bacterial gene involved in the formation of iron oxide nanocrystals, was genetically modified for in vivo monitoring of cell grafts by MRI. Inducible expression of MagA was regulated by a Tet-On (Tet) switch. A mouse embryonic stem cell-line carrying Tet-MagA (mESC-MagA) was established by lentivirus transduction. The impact of expressing MagA in mESCs was evaluated via proliferation assay, cytotoxicity assay, teratoma formation, MRI, and inductively coupled plasma atomic emission spectroscopy (ICP-OES). Mice were grafted with mESCs with and without MagA (mESC-MagA and mESC-WT). The condition of cell grafts with induced “ON” and non-induced “OFF” expression of MagA was longitudinally monitored in vivo using a 7T MRI scanner. After imaging, whole brain samples were harvested for histological assessment. Results: Expression of MagA in mESCs resulted in significant changes in the transverse relaxation rate (R2 or 1/T2) and susceptibility weighted MRI contrast. The pluripotency of mESCs carrying MagA was not affected in vitro or in vivo. Intracranial mESC-MagA grafts generated sufficient T2 and susceptibility weighted contrast at 7T. The mESC-MagA grafts can be monitored by MRI longitudinally upon induced expression of MagA by administering doxycycline (Dox) via diet. Conclusion: Our results demonstrate MagA could be used to monitor cell grafts noninvasively, longitudinally, and repetitively, enabling the assessment of cell graft conditions in vivo.
doi:10.7150/thno.9436
PMCID: PMC4143941  PMID: 25161700
Magnetic resonance imaging; reporter gene; MagA; longitudinal monitoring; stem cell; cell tracking; regenerative medicine; inducible expression; intracranial graft.
17.  Anti-HER2 antibody and ScFvEGFR-conjugated antifouling magnetic iron oxide nanoparticles for targeting and magnetic resonance imaging of breast cancer 
Antifouling magnetic iron oxide nanoparticles (IONPs) coated with block copolymer poly(ethylene oxide)-block-poly(γ-methacryloxypropyltrimethoxysilane) (PEO-b-PγMPS) were investigated for improving cell targeting by reducing nonspecific uptake. Conjugation of a HER2 antibody, Herceptin®, or a single chain fragment (ScFv) of antibody against epidermal growth factor receptor (ScFvEGFR) to PEO-b-PγMPS-coated IONPs resulted in HER2-targeted or EGFR-targeted IONPs (anti-HER2-IONPs or ScFvEGFR-IONPs). The anti-HER2-IONPs bound specifically to SK-BR-3, a HER2-overexpressing breast cancer cell line, but not to MDA-MB-231, a HER2-underexpressing cell line. On the other hand, the ScFvEGFR-IONPs showed strong reactivity with MDA-MB-231, an EGFR-positive human breast cancer cell line, but not with MDA-MB-453, an EGFR-negative human breast cancer cell line. Transmission electron microscopy revealed internalization of the receptor-targeted nanoparticles by the targeted cancer cells. In addition, both antibody-conjugated and non-antibody-conjugated IONPs showed reduced nonspecific uptake by RAW264.7 mouse macrophages in vitro. The developed IONPs showed a long blood circulation time (serum half-life 11.6 hours) in mice and low accumulation in both the liver and spleen. At 24 hours after systemic administration of ScFvEGFR-IONPs into mice bearing EGFR-positive breast cancer 4T1 mouse mammary tumors, magnetic resonance imaging revealed signal reduction in the tumor as a result of the accumulation of the targeted IONPs.
doi:10.2147/IJN.S49069
PMCID: PMC3794963  PMID: 24124366
magnetic nanoparticles; active targeting; antifouling; breast cancer; magnetic resonance imaging
18.  T1-Weighted Ultrashort Echo Time Method for Positive Contrast Imaging of Magnetic Nanoparticles and Cancer Cells Bound With the Targeted Nanoparticles 
Purpose
To obtain positive contrast based on T1 weighting from magnetic iron oxide nanoparticle (IONP) using ultrashort echo time (UTE) imaging and investigate quantitative relationship between positive contrast and the core size and concentration of IONPs.
Materials and Methods
Solutions of IONPs with different core sizes and concentrations were prepared. T1 and T2 relaxation times of IONPs were measured using the inversion recovery turbo spin echo (TSE) and multi-echo spin echo sequences at 3 Tesla. T1-weighted UTE gradient echo and T2-weighted TSE sequences were used to image IONP samples. U87MG glioblastoma cells bound with arginine-glycine-aspartic acid (RGD) peptide and IONP conjugates were scanned using UTE, T1 and T2-weighted sequences.
Results
Positive contrast was obtained by UTE imaging from IONPs with different core sizes and concentrations. The relative-contrast-to-water ratio of UTE images was three to four times higher than those of T2-weighted TSE images. The signal intensity increases as the function of the core size and concentration. Positive contrast was also evident in cell samples bound with RGD-IONPs.
Conclusion
UTE imaging allows for imaging of IONPs and IONP bound tumor cells with positive contrast and provides contrast enhancement and potential quantification of IONPs in molecular imaging applications.
doi:10.1002/jmri.22412
PMCID: PMC3785614  PMID: 21182139
magnetic nanoparticle; magnetic resonance imaging; iron oxide; ultrashort TE; molecular Imaging
20.  Treating liver cancer with antibiotics? 
Acta Pharmacologica Sinica  2013;34(8):989-990.
doi:10.1038/aps.2013.102
PMCID: PMC4003016  PMID: 23912552
21.  Perfusing chemotherapy by percutaneous lung puncture “holing” for pulmonary tuberculoma—a ten-year single center experience 
Journal of Thoracic Disease  2013;5(4):466-471.
Background
Pulmonary tuberculoma is a special form of secondary pulmonary tuberculosis, with a poor response to drug treatment. We used the method of drug administration via percutaneous lung puncture “holing” to treat pulmonary tuberculoma and observe its short- and long-term efficacy, summing up our 10-year clinical experience.
Methods
A total of 54 patients with pulmonary tuberculoma were included in this study. They themselves were taken as the control group. Three to six months of conventional anti-tuberculosis treatment was conducted firstly. Then those patients with no changes of sizes in tuberculoma were recommended to receive drug administration via percutaneous lung puncture. Isoniazid (INH, 0.1 g) and amikacin (AMK, 0.2 g) were injected into tuberculoma (once or twice per week, 10 times as a course of treatment).
Results
After two months of drug treatment by lung puncture, the sputum smear test showed the negative conversion rate of tubercle bacillus was 87% (13/15), and the positive conversion rate was 8% (3/39). The tuberculosis bacillus culture indicated that the negative conversion rate was 100% (7/7). The reexamination after one year showed the negative conversion rate of tubercle bacillus in the sputum smear test was 80% (4/5). About 58% (31/54) of tuberculoma disappeared or significantly reduced, in which, 40% (21/54) of tuberculoma disappeared. The tuberculoma diameter reduced from 3.6 cm × 2.8 cm to 1.7 cm × 1.1 cm on average. Side-effects included postoperative pneumothorax 9% (5/54), hemoptysis 7% (4/54) and fever 11% (6/54). A total of 34 patients were followed up for five years, and the disappearance rate of tuberculoma was up to 47% (16/34), with no recurrence.
Conclusions
The drug administration via percutaneous lung puncture—“holing” in pulmonary tuberculoma takes a significant effect obviously, good short- and long-term effects and less side effects.
doi:10.3978/j.issn.2072-1439.2013.07.03
PMCID: PMC3755674  PMID: 23991304
Percutaneous lung puncture; pulmonary tuberculoma; holing
22.  Biphasic catalysis using amphiphilic polyphenols-chelated noble metals as highly active and selective catalysts 
Scientific Reports  2013;3:2226.
In the field of catalysis, it is highly desired to develop novel catalysts that combine the advantages of both homogeneous and heterogeneous catalysts. Here we disclose that the use of plant pholyphenol as amphiphilic large molecule ligand/stabilizer allows for the preparation of noble metal complex and noble metal nanoparticle catalysts. These catalysts are found to be highly selective and active in aqueous-organic biphasic catalysis of cinnamaldehyde and quinoline, and can be reused at least 3 times without significant loss of activity. Moreover, the catalytic activity and reusability of the catalysts can be rationally controlled by simply adjusting the content of polyphenols in the catalysts. Our strategy may be extended to design a wide range of aqueous-organic biphasic catalysis system.
doi:10.1038/srep02226
PMCID: PMC3714648  PMID: 23863916
23.  Mechanisms of Siglec-F-Induced Eosinophil Apoptosis: A Role for Caspases but Not for SHP-1, Src Kinases, NADPH Oxidase or Reactive Oxygen 
PLoS ONE  2013;8(6):e68143.
Background
Siglec-F and Siglec-8 are functional paralog proapoptotic cell surface receptors expressed on mouse and human eosinophils, respectively. Whereas Siglec-8 mediated death involves caspases and/or reactive oxygen species (ROS) generation and mitochondrial injury, very little is known about Siglec-F-mediated signaling and apoptosis. Therefore the objective of the current experiments was to better define apoptosis pathways mediated by Siglec-F and Siglec-8. Given that Siglec-F-induced apoptosis is much less robust than Siglec-8-induced apoptosis, we hypothesized that mechanisms involved in cell death via these receptors would differ.
Methods
Consequences of engagement of Siglec-F on mouse eosinophils were studied by measuring ROS production, and by performing apoptosis assays using eosinophils from normal, hypereosinophilic, NADPH oxidase-deficient, src homology domain-containing protein tyrosine phosphatase (SHP)-1-deficient, and Lyn kinase-deficient mice. Inhibitors of caspase and Src family kinase activity were also used.
Results
Engagement of Siglec-F induced mouse eosinophil apoptosis that was modest in magnitude and dependent on caspase activity. There was no detectable ROS generation, or any role for ROS, NADPH oxidase, SHP-1, or Src family kinases in this apoptotic process.
Conclusions
These data suggest that Siglec-F-mediated apoptosis is different in both magnitude and mechanisms when compared to published data on Siglec-8-mediated human eosinophil apoptosis. One likely implication of this work is that models targeting Siglec-F in vivo in mice may not provide identical mechanistic predictions for consequences of Siglec-8 targeting in vivo in humans.
doi:10.1371/journal.pone.0068143
PMCID: PMC3695997  PMID: 23840825
24.  Dynamic change of SGK expression and its role in neuron apoptosis after traumatic brain injury 
Aims: Activation of specific signaling pathways in response to mechanical trauma causes delayed neuronal apoptosis; GSK-3β/β-catenin signaling plays a critical role in the apoptosis of neurons in CNS diseases, SGK was discovered as a regulator of GSK-3β/β-catenin pathway, The goal of this study was to determine if the mechanism of cell death or survival mediated by the SGK/GSK-3β/β-catenin pathway is involved in a rat model of TBI. Main methods: Here, an acute traumatic brain injury model was applied to investigate the expression change and possible roles of SGK, Expression of SGK, and total-GSK-3β, phospho-GSK3β on ser-9, beta-catenin, and caspase-3 were examined by immunohistochemistry and Western blot analysis. Double immunofluorescent staining was used to observe the SGK localizations. Si-RNA was performed to identify whether SGK regulates neuron apoptosis via GSK-3β/β-catenin pathway, ultimately inhibit caspase-3 activation. Key findings: Temporally, SGK expression showed an increase pattern after TBI and reached a peak at day 3. Spatially, SGK was widely expressed in the neuron, rarely in astrocytes and oligodendrocytes; in addition, the expression patterns of active caspase-3 and phospho-GSK3β were parallel with that of SGK, at the same time, the expression of β-catenin shows similarity with SGK. In vitro, to further investigate the function of SGK, a neuronal cell line PC12 was employed to establish an apoptosis model. We analyzed the association of SGK with apoptosis on PC12 cells by western blot, immunofluorescent labeling and siRNA. Significance: the results implied that SGK plays an important role in neuron apoptosis via the regulation of GSK3β/β-catenin signaling pathway; ultimately inhibit caspase-3 activation. Taken together, we inferred traumatic brain injury induced an upregulation of SGK in the central nervous system, which show a protective role in neuron apoptosis.
PMCID: PMC3693193  PMID: 23826409
SGK; GSK3β/β-catenin signaling pathway; traumatic brain injury (TBI); neuron apoptosis
25.  Molecular Imaging of Pancreatic Cancer in an Animal Model Using Targeted Multifunctional Nanoparticles 
Gastroenterology  2009;136(5):1514-25.e2.
Background & Aims
Identification of a ligand/receptor system that enables functionalized nanoparticles to efficiently target pancreatic cancer holds great promise for the development of novel approaches for the detection and treatment of pancreatic cancer. Urokinase plasminogen activator receptor (uPAR), a cellular receptor that is highly expressed in pancreatic cancer and tumor stromal cells, is an excellent surface molecule for receptor-targeted imaging of pancreatic cancer using multifunctional nanoparticles.
Methods
The uPAR-targeted dual-modality molecular imaging nanoparticle probe is designed and prepared by conjugating a near-infrared dye-labeled amino-terminal fragment of the receptor binding domain of urokinase plasminogen activator to the surface of functionalized magnetic iron oxide nanoparticles.
Results
We have shown that the systemic delivery of uPAR-targeted nanoparticles leads to their selective accumulation within tumors of orthotopically xenografted human pancreatic cancer in nude mice. The uPAR-targeted nanoparticle probe binds to and is subsequently internalized by uPAR-expressing tumor cells and tumor-associated stromal cells, which facilitates the intratumoral distribution of the nanoparticles and increases the amount and retention of the nanoparticles in a tumor mass. Imaging properties of the nanoparticles enable in vivo optical and magnetic resonance imaging of uPAR-elevated pancreatic cancer lesions.
Conclusions
Targeting uPAR using biodegradable multifunctional nanoparticles allows for the selective delivery of the nanoparticles into primary and metastatic pancreatic cancer lesions. This novel receptor-targeted nanoparticle is a potential molecular imaging agent for the detection of pancreatic cancer.
doi:10.1053/j.gastro.2009.01.006
PMCID: PMC3651919  PMID: 19208341

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