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1.  Magnetic microbubble-mediated ultrasound-MRI registration based on robust optical flow model 
BioMedical Engineering OnLine  2015;14(Suppl 1):S14.
As a dual-modality contrast agent, magnetic microbubbles (MMBs) can not only improve contrast of ultrasound (US) image, but can also serve as a contrast agent of magnetic resonance image (MRI). With the help of MMBs, a new registration method between US image and MRI is presented.
In this method, MMBs were used in both ultrasound and magnetic resonance imaging process to enhance the most important information of interest. In order to reduce the influence of the speckle noise to registration, semi-automatic segmentations of US image and MRI were carried out by using active contour model. After that, a robust optical flow model between US image segmentation (floating image) and MRI segmentation (reference image) was built, and the vector flow field was estimated by using the Coarse-to-fine Gaussian pyramid and graduated non-convexity (GNC) schemes.
Qualitative and quantitative analyses of multiple group comparison experiments showed that registration results using all methods tested in this paper without MMBs were unsatisfactory. On the contrary, the proposed method combined with MMBs led to the best registration results.
The proposed algorithm combined with MMBs contends with larger deformation and performs well not only for local deformation but also for global deformation. The comparison experiments also demonstrated that ultrasound-MRI registration using the above-mentioned method might be a promising method for obtaining more accurate image information.
PMCID: PMC4306103  PMID: 25602434
2.  A method of extending the depth of focus of the high-resolution X-ray imaging system employing optical lens and scintillator: a phantom study 
BioMedical Engineering OnLine  2015;14(Suppl 1):S15.
The high-resolution X-ray imaging system employing synchrotron radiation source, thin scintillator, optical lens and advanced CCD camera can achieve a resolution in the range of tens of nanometers to sub-micrometer. Based on this advantage, it can effectively image tissues, cells and many other small samples, especially the calcification in the vascular or in the glomerulus. In general, the thickness of the scintillator should be several micrometers or even within nanometers because it has a big relationship with the resolution. However, it is difficult to make the scintillator so thin, and additionally thin scintillator may greatly reduce the efficiency of collecting photons.
In this paper, we propose an approach to extend the depth of focus (DOF) to solve these problems. We develop equation sets by deducing the relationship between the high-resolution image generated by the scintillator and the degraded blur image due to defect of focus first, and then we adopt projection onto convex sets (POCS) and total variation algorithm to get the solution of the equation sets and to recover the blur image.
By using a 20 μm thick unmatching scintillator to replace the 1 μm thick matching one, we simulated a high-resolution X-ray imaging system and got a degraded blur image. Based on the algorithm proposed, we recovered the blur image and the result in the experiment showed that the proposed algorithm has good performance on the recovery of image blur caused by unmatching thickness of scintillator.
The method proposed is testified to be able to efficiently recover the degraded image due to defect of focus. But, the quality of the recovery image especially of the low contrast image depends on the noise level of the degraded blur image, so there is room for improving and the corresponding denoising algorithm is worthy for further study and discussion.
PMCID: PMC4306104  PMID: 25602532
3.  Enhanced cytotoxic activity of cetuximab in EGFR-positive lung cancer by conjugating with gold nanoparticles 
Scientific Reports  2014;4:7490.
Cetuximab (C225) is a unique agent, targeting epidermal growth factor receptor (EGFR)-positive cancer. However, the therapeutic effect of C225 in EGFR high-expressing non-small cell lung cancer (NSCLC) remains poor. Here, we report that conjugation of C225 with gold nanoparticles (AuNPs) enhances the cytotoxicity of C225 in NSCLC both in vitro and in vivo. The NSCLC cell lines A549 (EGFRhigh) and H1299 (EGFRlow) were employed to investigate different responses to C225, IgG-AuNPs and C225-AuNPs. The antitumor properties of C225-AuNPs were explored in vivo by establishing a tumor xenograft model in nude mice. Overall, the therapeutic effect of C225-AuNPs was more pronounced in EGFRhigh A549 cells compared with EGFRlow H1299 cells. The cytotoxic effect of C225-AuNPs in A549 cells increased in a dose-dependent manner. C225-AuNPs significantly suppressed A549 cell proliferation and migration capacity and accelerated apoptosis compared with C225, and this effect was probably due to enhanced EGFR endocytosis and the subsequent suppression of downstream signaling pathway. Finally in the tumor xenograft of nude mice, treatment with C225-AuNPs also led to a significant reduction in tumor weight and volume with low toxicity. Our findings suggest that C225-AuNPs conjugate has promising potential for targeted therapy of EGFR positive NSCLC patients.
PMCID: PMC4265789  PMID: 25502402
5.  Enhancement of radiosensitization by metal-based nanoparticles in cancer radiation therapy 
Cancer Biology & Medicine  2014;11(2):86-91.
Radiation therapy performs an important function in cancer treatment. However, resistance of tumor cells to radiation therapy still remains a serious concern, so the study of radiosensitizers has emerged as a persistent hotspot in radiation oncology. Along with the rapid advancement of nanotechnology in recent years, the potential value of nanoparticles as novel radiosensitizers has been discovered. This review summarizes the latest experimental findings both in vitro and in vivo and attempts to highlight the underlying mechanisms of response in nanoparticle radiosensitization.
PMCID: PMC4069802  PMID: 25009750
Nanoparticles; radiation tolerance; cancer; radiotherapy
6.  Magnetic assembly-mediated enhancement of differentiation of mouse bone marrow cells cultured on magnetic colloidal assemblies 
Scientific Reports  2014;4:5125.
Here we reported an interesting phenomenon that the field-induced assemblies of magnetic nanoparticles can promote the differentiation of primary mouse bone marrow cells into osteoblasts. The reason was thought to lie in the remnant magnetic interaction inside the assemblies which resulted from the magnetic field-directed assembly. Influence of the assemblies on the cells was realized by means of interface effect rather than the internalization effect. We fabricated a stripe-like assemblies array on the glass plate and cultured cells on this surface. We characterized the morphology of assemblies and measured the mechanic property as well as the magnetic property. The cellular differentiation was measured by staining and quantitative PCR. Finally, Fe uptake was excluded as the reason to cause the phenomenon.
PMCID: PMC4038806  PMID: 24874764
7.  Magnetic fluid hyperthermia inhibits the growth of breast carcinoma and downregulates vascular endothelial growth factor expression 
Oncology Letters  2014;7(5):1370-1374.
The application of magnetic fluid hyperthermia (MFH) with nanoparticles has been shown to inhibit tumor growth in several animal models. However, the feasibility of using MFH in vivo to treat breast cancer is uncertain, and the mechanism is unclear. In the present study, it was observed that the intratumoral administration of MFH induced hyperthermia significantly in rats with Walker-265 breast carcinomas. The hyperthermia treatment with magnetic nanoparticles inhibited tumor growth in vivo and promoted the survival of the tumor-bearing rats. Furthermore, it was found that MFH treatment downregulated the protein expression of vascular endothelial growth factor (VEGF) in the tumor tissue, as observed by immunohistochemistry. MFH treatment also decreased the gene expression of VEGF and its receptors, VEGF receptor 1 and 2, and inhibited angiogenesis in the tumor tissues. Taken together, these results indicate that the application of MFH with nanoparticles is feasible for the treatment of breast carcinoma. The MFH-induced downregulation of angiogenesis may also contribute to the induction of an anti-tumor effect.
PMCID: PMC3997720  PMID: 24765139
breast carcinoma; thermotherapy; magnetic nanoparticle; vascular endothelial growth factor; angiogenesis
8.  Eliciting health state utilities for Dupuytren’s contracture using a discrete choice experiment 
Acta Orthopaedica  2013;84(6):571-578.
Background and purpose
An internet-based discrete choice experiment (DCE) was conducted to elicit preferences for a wide range of Dupuytren’s contracture (DC)-related health states. An algorithm was subsequently developed to convert these preferences into health state utilities that can be used to assess DC’s impact on quality of life and the value of its treatments.
Health state preferences for varying levels of DC hand severity were elicited via an internet survey from a sample of the UK adult population. Severity levels were defined using a combination of contractures (0, 45, or 90 degrees) in 8 proximal interphalangeal and metacarpophalangeal joints of the index, middle, ring, and little fingers. Right-handed, left-handed, and ambidextrous respondents indicated which hand was preferable in each of the 10 randomly-selected hand-pairings comparing different DC severity levels. For consistency across comparisons, anatomically precise digital hand drawings were used. To anchor preferences onto the traditional 0–1 utility scale used in health economic evaluations, unaffected hands were assigned a utility of 1.0 whereas the utility for a maximally affected hand (i.e., all 8 joints set at 90 degrees of contracture) was derived by asking respondents to indicate what combination of attributes and levels of the EQ-5D-5L profile most accurately reflects the impact of living with such hand. Conditional logistic models were used to estimate indirect utilities, then rescaled to the anchor points on the EQ-5D-5L.
Estimated utilities based on the responses of 1,745 qualified respondents were 0.49, 0.57, and 0.63 for completely affected dominant hands, non-dominant hands, or ambidextrous hands, respectively. Utility for a dominant hand with 90-degree contracture in t h e metacarpophalangeal joints of the ring and little fingers was estimated to be 0.89. Separately, reducing the contracture of metacarpophalangeal joint for a little finger from 50 to 12 degrees would improve utility by 0.02.
DC is associated with substantial utility decre- ments. The algorithms presented herein provide a robust and flexible framework to assess utility for varying degrees of DC severity.
PMCID: PMC3851672  PMID: 24286567
9.  Super-paramagnetic responsive nanofibrous scaffolds under static magnetic field enhance osteogenesis for bone repair in vivo 
Scientific Reports  2013;3:2655.
A novel nanofibrous composite scaffold composed of super-paramagnetic γ-Fe2O3 nanoparticles (MNP), hydroxyapatite nanoparticles (nHA) and poly lactide acid (PLA) was prepared using electrospinning technique. The scaffold well responds extern static magnetic field with typical saturation magnetization value of 0.049 emu/g as well as possesses nanofibrous architecture. The scaffolds were implanted in white rabbit model of lumbar transverse defects. Permanent magnets are fixed in the rabbit cages to provide static magnetic field for the rabbits post surgery. Results show that MNP incorporated in the nanofibers endows the scaffolds super-paramagnetic responsive under the applied static magnetic field, which accelerates new bone tissue formation and remodeling in the rabbit defect. The scaffold also exhibits good compatibility of CK, Cr, ALT and ALP within normal limits in the serum within 110 days post implantation. In conclusion, the super-paramagnetic responding scaffold with applying of external magnetic field provides a novel strategy for scaffold-guided bone repair.
PMCID: PMC3772377  PMID: 24030698
10.  The cytotoxicity evaluation of magnetic iron oxide nanoparticles on human aortic endothelial cells 
Nanoscale Research Letters  2013;8(1):215.
One major obstacle for successful application of nanoparticles in medicine is its potential nanotoxicity on the environment and human health. In this study, we evaluated the cytotoxicity effect of dimercaptosuccinic acid-coated iron oxide (DMSA-Fe2O3) using cultured human aortic endothelial cells (HAECs). Our results showed that DMSA-Fe2O3 in the culture medium could be absorbed into HAECs, and dispersed in the cytoplasm. The cytotoxicity effect of DMSA-Fe2O3 on HAECs was dose-dependent, and the concentrations no more than 0.02 mg/ml had little toxic effect which were revealed by tetrazolium dye assay. Meanwhile, the cell injury biomarker, lactate dehydrogenase, was not significantly higher than that from control cells (without DMSA-Fe2O3). However, the endocrine function for endothelin-1 and prostacyclin I-2, as well as the urea transporter function, was altered even without obvious evidence of cell injury in this context. We also showed by real-time PCR analysis that DMSA-Fe2O3 exposure resulted in differential effects on the expressions of pro- and anti-apoptosis genes of HAECs. Meanwhile, it was noted that DMSA-Fe2O3 exposure could activate the expression of genes related to oxidative stress and adhesion molecules, which suggested that inflammatory response might be evoked. Moreover, we demonstrated by in vitro endothelial tube formation that even a small amount of DMSA-Fe2O3 (0.01 and 0.02 mg/ml) could inhibit angiogenesis by the HAECs. Altogether, these results indicate that DMSA-Fe2O3 have some cytotoxicity that may cause side effects on normal endothelial cells.
PMCID: PMC3651330  PMID: 23647620
Magnetic nanoparticles; Iron oxide; Endothelial cells; Cell viability; Angiogenesis
11.  Paclitaxel-Fe3O4 nanoparticles inhibit growth of CD138− CD34− tumor stem-like cells in multiple myeloma-bearing mice 
There is growing evidence that CD138− CD34− cells may actually be tumor stem cells responsible for initiation and relapse of multiple myeloma. However, effective drugs targeted at CD138− CD34− tumor stem cells are yet to be developed. The purpose of this study was to investigate the inhibitory effect of paclitaxel-loaded Fe3O4 nanoparticles (PTX-NPs) on CD138− CD34− tumor stem cells in multiple myeloma-bearing mice.
CD138− CD34− cells were isolated from a human U266 multiple myeloma cell line using an immune magnetic bead sorting method and then subcutaneously injected into mice with nonobese diabetic/severe combined immunodeficiency to develop a multiple myeloma-bearing mouse model. The mice were treated with Fe3O4 nanoparticles 2 mg/kg, paclitaxel 4.8 mg/kg, and PTX-NPs 0.64 mg/kg for 2 weeks. Tumor growth, pathological changes, serum and urinary interleukin-6 levels, and molecular expression of caspase-3, caspase-8, and caspase-9 were evaluated.
CD138− CD34− cells were found to have tumor stem cell characteristics. All the mice developed tumors in 40 days after injection of 1 × 106 CD138− CD34− tumor stem cells. Tumor growth in mice treated with PTX-NPs was significantly inhibited compared with the controls (P < 0.005), and the groups that received nanoparticles alone (P < 0.005) or paclitaxel alone (P < 0.05). In addition, the PTX-NPs markedly inhibited interleukin-6 secretion, increased caspase-8, caspase-9, and caspase-3 expression, and induced apoptosis of tumor cells in the treated mice.
PTX-NPs proved to be a potent anticancer treatment strategy that may contribute to targeted therapy for multiple myeloma tumor stem cells in future clinical trials.
PMCID: PMC3629869  PMID: 23610522
multiple myeloma; tumor stem cells; Fe3O4 nanoparticles; paclitaxel
12.  γ-tocotrienol attenuates TNF-α-induced changes in secretion and gene expression of MCP-1, IL-6 and adiponectin in 3T3-L1 adipocytes 
Molecular Medicine Reports  2012;5(4):905-909.
Tocotrienols, members of the vitamin E family, have been shown to possess anti-inflammatory properties and display activity against a variety of chronic diseases, such as cancer, cardiovascular and neurological diseases. However, whether tocotrienols contribute to the prevention of inflammatory responses in adipose tissue remains to be elucidated. In this study, we examined the effects of γ-tocotrienol, the most common tocotrienol isomer, on tumor necrosis factor-α (TNF-α)-induced inflammatory responses by measuring the expression of the adipokines, monocyte chemoattractant protein-1 (MCP-1), interleukin-6 (IL-6) and adiponectin in 3T3-L1 adipocytes. Exposure to TNF-α (10 ng/ml) for 24 h increased MCP-1 and IL-6 secretion, and decreased adiponectin secretion and peroxisome proliferator-activated receptor-γ (PPARγ) mRNA expression. γ-tocotrienol effectively improved the TNF-α-induced adverse changes in MCP-1, IL-6 and adiponectin secretion, and in MCP-1, IL-6, adiponectin and PPARγ mRNA expression. Furthermore, TNF-α-mediated IκB-α phosphorylation and nuclear factor-κB (NF-κB) activation were significantly suppressed by the γ-tocotrienol treatment. Our results suggest that γ-tocotrienol may improve obesity-related functional abnormalities in adipocytes by attenuating NF-κB activation and the expression of inflammatory adipokines.
PMCID: PMC3493080  PMID: 22293775
tocotrienol; vitamin E; adipocyte; adipokine; inflammation
13.  Exploiting BSA to Inhibit the Fibrous Aggregation of Magnetic Nanoparticles under an Alternating Magnetic Field 
The alternating magnetic field was discovered to be capable of inducing the fibrous aggregation of magnetic nanoparticles. However, this anisotropic aggregation may be unfavorable for practical applications. Here, we reported that the adsorption of BSA (bovine serum albumin) on the surfaces of magnetic nanoparticles can effectively make the fibrous aggregation of γ-Fe2O3 nanoparticles turn into a more isotropic aggregation in the presence of the alternating magnetic field. Also, the heating curves with and without BSA adsorption under different pH conditions were measured to show the influence of the colloidal aggregation states on the collective calorific behavior of magnetic nanoparticles.
PMCID: PMC3634418  PMID: 23481639
alternating magnetic field; colloidal assembly; biomolecule; bioelectronics
14.  Facile synthesis of ultrathin magnetic iron oxide nanoplates by Schikorr reaction 
In this work, a very facile one-pot hydrothermal synthesis approach has been developed for the preparation of ultrathin magnetite nanoplates. The hydrothermal procedure was performed by aging ferrous hydroxide under anaerobic conditions, which is known as Schikorr reaction. Ethylene glycol (EG), which was introduced to the reaction as another solvent, played a critical role in the formation process of these nanoplates. Typically, hexagonal Fe3O4 nanoplates with a thickness of 10 to 15 nm and a side length of 150 to 200 nm have been synthesized with EG/H2O = 1:1 in experiments. Our data suggest that the thickness of Fe3O4 nanoplates decreases, and the shape of the nanoplate becomes more irregular when the concentration of EG increases. The as-prepared Fe3O4 nanoplates were highly crystallized single crystals and exhibited large coercivity and specific absorption rate coefficient.
PMCID: PMC3598988  PMID: 23294626
Magnetite nanoplates; Schikorr reaction; Ethylene glycol; Ferrous hydroxide
16.  Improved performance of diatomite-based dental nanocomposite ceramics using layer-by-layer assembly 
To fabricate high-strength diatomite-based ceramics for dental applications, the layer-by-layer technique was used to coat diatomite particles with cationic [poly(allylamine hydrochloride)] and anionic [poly(sodium 4-styrenesulfonate)] polymers to improve the dispersion and adsorption of positively charged nano-ZrO2 (zirconia) as a reinforcing agent. The modified diatomite particles had reduced particle size, narrower size distribution, and were well dispersed, with good adsorption of nano-ZrO2. To determine the optimum addition levels for nano-ZrO2, ceramics containing 0, 20, 25, 30, and 35 wt% nano-ZrO2 were sintered and characterized by the three-point bending test and microhardness test. In addition to scanning electron microscopy, propagation phase-contrast synchrotron X-ray microtomography was used to examine the internal structure of the ceramics. The addition of 30 wt% nano-ZrO2 resulted in the highest flexural strength and fracture toughness with reduced porosity. Shear bond strength between the core and veneer of our diatomite ceramics and the most widely used dental ceramics were compared; the shear bond strength value for the diatomite-based ceramics was found to be significantly higher than for other groups (P < 0.05). Our results show that diatomite-based nanocomposite ceramics are good potential candidates for ceramic-based dental materials.
PMCID: PMC3356216  PMID: 22619551
layer-by-layer; diatomite; nanoceramics; zirconia (ZrO2); dental materials
17.  Ferritin Enhances SPIO Tracking of C6 Rat Glioma Cells by MRI 
To investigate the effect of ferritin protein overexpression on superparamagnetic iron oxide (SPIO) particle labeling of C6 rat glioma cells, and track the labeled cells in vivo using magnetic resonance imaging (MRI).
Materials and Methods
A plasmid of H-chain of murine ferritin gene was constructed and transfected into C6 cells. The parental and the transfected C6 cells labeled with SPIO were bilaterally inoculated subcutaneously into nude mice. The mice were imaged by multiple T2-weighted MR scans after C6 cell inoculation. The mice were killed 2 weeks later, and the concentration of iron in the tumor tissue was measured by inductively coupled plasma.
The iron concentration in xenografts derived from SPIO-labeled C6 cells that were transfected with ferritin plasmid was significantly higher than that in xenografts from parental C6 cells that were labeled with SPIO but not transfected (p=0.034, N=5). Ferritin-transfected C6 cells showed an improved T2 contrast in vivo compared with parental cells labeled with SPIO but not transfected.
Coordinating ferritin with SPIO can lead to a longer MRI cellular tracking period.
PMCID: PMC2966504  PMID: 20440566
Ferritin reporter; Superparamagnetic iron oxide (SPIO) particle; Cell tracking; MRI
18.  Applications of Magnetic Microbubbles for Theranostics 
Theranostics  2012;2(1):103-112.
Compared with other diagnostic methods, ultrasound is proven to be a safe, simple, non-invasive and cost-effective imaging technique, but the resolution is not comparable to that of magnetic resonance imaging (MRI). Contrast-enhanced ultrasound employing microbubbles can gain a better resolution and is now widely used to diagnose a number of diseases in the clinic. For the last decade, microbubbles have been widely used as ultrasound contrast agents, drug delivery systems and nucleic acid transfection tools. However, microbubbles are not fairly stable enough in some conditions and are not well administrated distributed in the circulation system. On the other hand, magnetic nanoparticles, as MRI contrast agents, can non-specifically penetrate into normal tissues because of their relatively small sizes. By taking advantage of these two kinds of agents, the magnetic microbubbles which couple magnetic iron oxides nanoparticles in the microbubble structure have been explored. The stability of microbubbles can be raised by encapsulating magnetic nanoparticles into the bubble shells and with the guidance of magnetic field, magnetic microbubbles can be delivered to regions of interest, and after appropriate ultrasound exposure, the nanoparticles can be released to the desired area while the magnetic microbubbles collapse. In this review, we summarize magnetic microbubbles used in diagnostic and therapeutic fields, and predict the potential applications of magnetic microbubbles in the future.
PMCID: PMC3267385  PMID: 22287990
Magnetic microbubble; Dual-modality imaging; Drug delivery system; Molecular imaging.
19.  Mapping of the Insomnia Severity Index and other sleep measures to EuroQol EQ-5D health state utilities 
This study sought to map the Insomnia Severity Index (ISI) and symptom variables onto the EQ-5D.
A cross-sectional survey was conducted among adult US residents with self-reported sleep problems. Respondents provided demographic, comorbidity, and sleep-related information and had completed the ISI and the EQ-5D profile. Respondents were classified into ISI categories indicating no, threshold, moderate, or severe insomnia. Generalized linear models (GLM) were used to map the ISI's 7 items (Model I), summary scores (Model II), clinical categories (Model III), and insomnia symptoms (Model IV), onto the EQ-5D. We used 50% of the sample for estimation and 50% for prediction. Prediction accuracy was assessed by mean squared errors (MSEs) and mean absolute errors (MAEs).
Mean (standard deviation) sleep duration for respondents (N = 2,842) was 7.8 (1.9) hours, and mean ISI score was 14.1 (4.8). Mean predicted EQ-5D utility was 0.765 (0.08) from Models I-III, which overlapped with observed utilities 0.765 (0.18). Predicted utility using insomnia symptoms was higher (0.771(0.07)). Based on Model I, predicted utilities increased linearly with improving ISI (0.493 if ISI = 28 vs. 1.00 if ISI = 0, p < 0.01). From Model II, each unit decrease in ISI summary score was associated with a 0.022 (p < 0.001) increase in utility. Predicted utilities were 0.868, 0.809, 0.722, and 0.579, respectively, for the 4 clinical categories, suggesting that lower utility was related to greater insomnia severity. The symptom model (Model IV) indicated a concave sleep-duration function of the EQ-5D; thus, utilities diminished after an optimal amount of sleep. The MSEs/MAEs were substantially lower when predicting EQ-5D > 0.40, and results were comparable in all models.
Findings suggest that mapping relationships between the EQ-5D and insomnia measures could be established. These relationships may be used to estimate insomnia-related treatment effects on health state utilities.
PMCID: PMC3377917  PMID: 22208861
Insomnia; Mapping; Insomnia Severity Index; EQ-5D
20.  The investigation of frequency response for the magnetic nanoparticulate assembly induced by time-varied magnetic field 
Nanoscale Research Letters  2011;6(1):453.
The field-induced assembly of γ-Fe2O3 nanoparticles under alternating magnetic field of different frequency was investigated. It was found that the assembly was dependent upon the difference between colloidal relaxation time and field period. The same experiments on DMSA-coated γ-Fe2O3 nanoparticles exhibited that the relaxation time may be mainly determined by the magnetic size rather than the physical size. Our results may be valuable for the knowledge of dynamic assembly of colloidal particles.
PMCID: PMC3211873  PMID: 21756332
magnetic field; dynamic assembly; pattern formation; magnetic nanoparticles
21.  Antitumor efficacy induced by a B16F10 tumor cell vaccine treated with mitoxantrone alone or in combination with reserpine and verapamil in mice 
An apoptotic tumor cell serves as a potential potent trigger for the initiation of naturally occurring tumor immunity. In the present study, a B16F10 tumor cell vaccine treated with mitoxantrone (MIT) was developed, and its antitumor effect on mice was evaluated. The results indicated that the B16F10 tumor cell vaccine treated with MIT alone or in combination with reserpine (RP) and verapamil (VP) for 12 h triggered apoptosis, and that the expression of CD80, the MHC II class molecule, NKG2D and its ligand were significantly increased compared to the expression levels in the control group. The tumor vaccine immunogenicity was significantly enhanced in the vaccinated mice, resulting in augmented cytotoxicity of splenocytes and NK cells as well as the splenocyte proliferative response compared to the control group mice. Notably, the mice vaccinated with the B16F10 tumor cell vaccine treated with MIT, RP and VP did not generate tumors only after 60 days into the observation, but the mice also generated a powerful immune prophylactic efficiency against the B16F10 tumor cell challenge. These findings demonstrated the safety and efficacy of the B16F10 tumor cell vaccine treated with MIT alone or in combination with RP and VP in the murine model, and suggest that an apoptotic tumor cell vaccine modeled on naturally occurring tumor immune responses in vivo may provide a safe and immunogenic tumor vaccine for potential applications in humans.
PMCID: PMC3440719  PMID: 22977597
tumor vaccine; mitoxantrone; apoptotic cells; reserpine; verapamil
22.  PGC-1α mRNA Level and Oxidative Capacity of the Plantaris Muscle in Rats with Metabolic Syndrome, Hypertension, and Type 2 Diabetes 
We examined the fiber profiles and the mRNA levels of peroxisome proliferator-activated receptors (PPARα and PPARδ/β) and of the PPARγ coactivator-1α (PGC-1α) in the plantaris muscles of 15-week-old control (WR), metabolic syndrome (CP), hypertensive (SHR), and type 2 diabetic (GK) rats. The deep regions in the muscles of SHR and GK rats exhibited lower percentages of high-oxidative type I and IIA fibers and higher percentages of low-oxidative type IIB fibers compared with WR and CP rats. The surface regions in the muscles of CP, SHR, and GK rats exhibited lower percentages of high-oxidative type IIA fibers and higher percentages of low-oxidative type IIB fibers compared with WR rats. The muscles of SHR and GK rats had lower oxidative enzyme activity compared with WR rats. The muscles of SHR rats had the lowest PPARδ/β mRNA level. In addition, the muscles of SHR and GK rats had lower PGC-1α mRNA level compared with WR and CP rats. We concluded that the plantaris muscles of rats with hypertension and type 2 diabetes have lower oxidative capacity, which is associated with the decreased level of PGC-1α mRNA.
PMCID: PMC3096084  PMID: 21614168
hypertension; oxidative capacity; PGC-1α mRNA; plantaris muscle; type 2 diabetes
23.  Arterial Embolization Hyperthermia Using As2O3 Nanoparticles in VX2 Carcinoma–Induced Liver Tumors 
PLoS ONE  2011;6(3):e17926.
Combination therapy for arterial embolization hyperthermia (AEH) with arsenic trioxide (As2O3) nanoparticles (ATONs) is a novel treatment for solid malignancies. This study was performed to evaluate the feasibility and therapeutic effect of AEH with As2O3 nanoparticles in a rabbit liver cancer model. The protocol was approved by our institutional animal use committee.
Methodology/Principal Findings
In total, 60 VX2 liver-tumor-bearing rabbits were randomly assigned to five groups (n = 12/group) and received AEH with ATONs (Group 1), hepatic arterial embolization with ATONs (Group 2), lipiodol (Group 3), or saline (Group 4), on day 14 after tumor implantation. Twelve rabbits that received AEH with ATONs were prepared for temperature measurements, and were defined as Group 5. Computed tomography was used to measure the tumors' longest dimension, and evaluation was performed according to the Response Evaluation Criteria in Solid Tumors. Hepatic toxicity, tumor necrosis rate, vascular endothelial growth factor level, and microvessel density were determined. Survival rates were measured using the Kaplan-Meier method. The therapeutic temperature (42.5°C) was obtained in Group 5. Hepatotoxicity reactions occurred but were transient in all groups. Tumor growth was delayed and survival was prolonged in Group 1 (treated with AEH and ATONs). Plasma and tumor vascular endothelial growth factor and microvessel density were significantly inhibited in Group 1, while tumor necrosis rates were markedly enhanced compared with those in the control groups.
ATON-based AEH is a safe and effective treatment that can be targeted at liver tumors using the dual effects of hyperthermia and chemotherapy. This therapy can delay tumor growth and noticeably inhibit tumor angiogenesis.
PMCID: PMC3063167  PMID: 21448278
24.  Neuronal Ca2+-Activated K+ Channels Limit Brain Infarction and Promote Survival 
PLoS ONE  2010;5(12):e15601.
Neuronal calcium-activated potassium channels of the BK type are activated by membrane depolarization and intracellular Ca2+ ions. It has been suggested that these channels may play a key neuroprotective role during and after brain ischemia, but this hypothesis has so far not been tested by selective BK-channel manipulations in vivo. To elucidate the in vivo contribution of neuronal BK channels in acute focal cerebral ischemia, we performed middle cerebral artery occlusion (MCAO) in mice lacking BK channels (homozygous mice lacking the BK channel alpha subunit, BK−/−). MCAO was performed in BK−/− and WT mice for 90 minutes followed by a 7-hour-reperfusion period. Coronal 1 mm thick sections were stained with 2,3,5-triphenyltetrazolium chloride to reveal the infarction area. We found that transient focal cerebral ischemia by MCAO produced larger infarct volume, more severe neurological deficits, and higher post-ischemic mortality in BK−/− mice compared to WT littermates. However, the regional cerebral blood flow was not significantly different between genotypes as measured by Laser Doppler (LD) flowmetry pre-ischemically, intra-ischemically, and post-ischemically, suggesting that the different impact of MCAO in BK−/− vs. WT was not due to vascular BK channels. Furthermore, when NMDA was injected intracerebrally in non-ischemic mice, NMDA-induced neurotoxicity was found to be larger in BK−/− mice compared to WT. Whole-cell patch clamp recordings from CA1 pyramidal cells in organotypic hippocampal slice cultures revealed that BK channels contribute to rapid action potential repolarization, as previously found in acute slices. When these cultures were exposed to ischemia-like conditions this induced significantly more neuronal death in BK−/− than in WT cultures. These results indicate that neuronal BK channels are important for protection against ischemic brain damage.
PMCID: PMC3012709  PMID: 21209897
25.  Manufacture of IRDye800CW-coupled Fe3O4 nanoparticles and their applications in cell labeling and in vivo imaging 
In recent years, near-infrared fluorescence (NIRF)-labeled iron nanoparticles have been synthesized and applied in a number of applications, including the labeling of human cells for monitoring the engraftment process, imaging tumors, sensoring the in vivo molecular environment surrounding nanoparticles and tracing their in vivo biodistribution. These studies demonstrate that NIRF-labeled iron nanoparticles provide an efficient probe for cell labeling. Furthermore, the in vivo imaging studies show excellent performance of the NIR fluorophores. However, there is a limited selection of NIRF-labeled iron nanoparticles with an optimal wavelength for imaging around 800 nm, where tissue autofluorescence is minimal. Therefore, it is necessary to develop additional alternative NIRF-labeled iron nanoparticles for application in this area.
This study manufactured 12-nm DMSA-coated Fe3O4 nanoparticles labeled with a near-infrared fluorophore, IRDye800CW (excitation/emission, 774/789 nm), to investigate their applicability in cell labeling and in vivo imaging. The mouse macrophage RAW264.7 was labeled with IRDye800CW-labeled Fe3O4 nanoparticles at concentrations of 20, 30, 40, 50, 60, 80 and 100 μg/ml for 24 h. The results revealed that the cells were efficiently labeled by the nanoparticles, without any significant effect on cell viability. The nanoparticles were injected into the mouse via the tail vein, at dosages of 2 or 5 mg/kg body weight, and the mouse was discontinuously imaged for 24 h. The results demonstrated that the nanoparticles gradually accumulated in liver and kidney regions following injection, reaching maximum concentrations at 6 h post-injection, following which they were gradually removed from these regions. After tracing the nanoparticles throughout the body it was revealed that they mainly distributed in three organs, the liver, spleen and kidney. Real-time live-body imaging effectively reported the dynamic process of the biodistribution and clearance of the nanoparticles in vivo.
IRDye800CW-labeled Fe3O4 nanoparticles provide an effective probe for cell-labeling and in vivo imaging.
PMCID: PMC2984479  PMID: 21034487

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