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1.  Non-invasive, Multimodal Functional Imaging of the Intestine with Frozen Micellar Naphthalocyanines 
Nature nanotechnology  2014;9(8):631-638.
There is a need for safer and improved methods for non-invasive imaging of the gastrointestinal tract. Modalities based on X-ray radiation, magnetic resonance and ultrasound suffer from limitations with respect to safety, accessibility or lack of adequate contrast. Functional intestinal imaging of dynamic gut processes has not been practical using existing approaches. Here, we report the development of a family of nanoparticles that can withstand the harsh conditions of the stomach and intestine, avoid systemic absorption, and give rise to good optical contrast for photoacoustic imaging. The hydrophobicity of naphthalocyanine dyes was exploited to generate purified ~20 nm frozen micelles, which we call nanonaps, with tunable and large near-infrared absorption values (>1000). Unlike conventional chromophores, nanonaps exhibited non-shifting spectra at ultrahigh optical densities and, following oral administration in mice, passed safely through the gastrointestinal tract. Non-invasive, non-ionizing photoacoustic techniques were used to visualize nanonap intestinal distribution with low background and remarkable resolution with 0.5 cm depth, and enabled real-time intestinal functional imaging with ultrasound co-registration. Positron emission tomography following seamless nanonap radiolabelling allowed complementary whole body imaging.
PMCID: PMC4130353  PMID: 24997526
2.  Relationship between red blood cell distribution width and intermediate-term mortality in elderly patients after percutaneous coronary intervention 
Large-scale clinical research on the relationship between red blood cell distribution width (RDW) and intermediate-term prognosis in elderly patients with coronary artery disease (CAD) is lacking. Thus, this study investigated the effects of RDW on the intermediate-term mortality of elderly patients who underwent elective percutaneous coronary intervention (PCI).
Data from 1891 patients ≥ 65 years old underwent elective PCI from July 2009 to September 2011 were collected. Based on preoperative median RDW (12.3%), the patients were divided into two groups. The low RDW group (RDW < 12.3%) had 899 cases; the high RDW group (RDW ≥ 12.3%) had 992 cases. The all-cause mortality rates of the two groups were compared.
Patients in the high RDW group were more likely to be female and accompanied with diabetes, had lower hemoglobin level. The mean follow-up period was 527 days. During follow-up, 61 patients died (3.2%). The postoperative mortality of the high RDW group was significantly higher than that of the low RDW group (4.3% vs. 2.0%, P = 0.004). After adjusting other factors, multivariate Cox regression analysis revealed that preoperative high RDW was significantly associated with postoperative all-cause mortality (hazard ratio: 2.301, 95% confidence interval: 1.106–4.785, P = 0.026).
Increased RDW was an independent predictor of the increased intermediate-term all-cause mortality in elderly CAD patients after elective PCI.
PMCID: PMC4308454
Coronary artery disease; Elderly patients; Percutaneous coronary intervention; Red blood cell distribution width
3.  Chelator-Free Synthesis of a Dual-Modality PET/MRI Agent 
Angewandte Chemie (International ed. in English)  2013;52(50):10.1002/anie.201306306.
PMCID: PMC3855680  PMID: 24166933
radioarsenic; SPION; PET; MRI; lymph node mapping; multimodality imaging
4.  Multimodality Imaging of CXCR4 in Cancer: Current Status towards Clinical Translation 
Current molecular medicine  2013;13(10):1538-1548.
CXCR4 has gained tremendous attention over the last decade, since it was found to be up-regulated in a wide variety of cancer types, in addition to its role in human immunodeficiency virus infection. Molecular imaging of CXCR4 with small molecules, peptides, and antibodies has been a vibrant research area over the last several years. In this review article, we will summarize the current status of imaging CXCR4 with fluorescence, bioluminescence, positron emission tomography, and single-photon emission computed tomography techniques. Since each molecular imaging modality has its own strengths and weaknesses, dual-modality probes that can be detected by more than one imaging techniques have also been investigated. Non-invasive visualization of CXCR4 expression has potential clinical applications in multiple facets of patient management. While big strides have been made over the last several years in the development of CXCR4-targeted imaging probes, clinical translation and investigation of these agents in cancer patients are eagerly awaited. Since CXCR4 is also involved in many other diseases beyond cancer, these clinically translatable probes can also play multiple roles in other pathological disorders such as myocardial infarction and several immunodeficiency disorders.
PMCID: PMC3838476  PMID: 24206137
CXCR4; molecular imaging; positron emission tomography (PET); metastasis; chemokine receptor; chemokine; cancer
5.  Biomedical Applications of Zinc Oxide Nanomaterials 
Current molecular medicine  2013;13(10):1633-1645.
Nanotechnology has witnessed tremendous advancement over the last several decades. Zinc oxide (ZnO), which can exhibit a wide variety of nanostructures, possesses unique semiconducting, optical, and piezoelectric properties hence has been investigated for a wide variety of applications. One of the most important features of ZnO nanomaterials is low toxicity and biodegradability. Zn2+ is an indispensable trace element for adults (~10 mg of Zn2+ per day is recommended) and it is involved in various aspects of metabolism. Chemically, the surface of ZnO is rich in -OH groups, which can be readily functionalized by various surface decorating molecules. In this review article, we summarized the current status of the use of ZnO nanomaterials for biomedical applications, such as biomedical imaging (which includes fluorescence, magnetic resonance, positron emission tomography, as well as dual-modality imaging), drug delivery, gene delivery, and biosensing of a wide array of molecules of interest. Research in biomedical applications of ZnO nanomaterials will continue to flourish over the next decade, and much research effort will be needed to develop biocompatible/biodegradable ZnO nanoplatforms for potential clinical translation.
PMCID: PMC3838497  PMID: 24206130
Zinc oxide; molecular imaging; cancer; nanosensor; drug delivery; gene delivery; personalized medicine
6.  Antibody-Based Imaging of HER-2: Moving into the Clinic 
Current molecular medicine  2013;13(10):1523-1537.
Human epidermal growth factor receptor-2 (HER-2) mediates a number of important cellular activities, and is up-regulated in a diverse set of cancer cell lines, especially breast cancer. Accordingly, HER-2 has been regarded as a common drug target in cancer therapy. Antibodies can serve as ideal candidates for targeted tumor imaging and drug delivery, due to their inherent affinity and specificity. Advanced by the development of a wide variety of imaging techniques, antibody-based imaging of HER-2 can allow for early detection and localization of tumors, as well as monitoring of drug delivery and tissue’s response to drug treatment. In this review article, antibody-based imaging of HER-2 are summarized and discussed, with an emphasis on the involved imaging methods.
PMCID: PMC3852915  PMID: 24206138
Antibody; Drug delivery; Radioimmunoscintigraphy (RIS); Positron emission tomography (PET); Single-photon emission computed tomography (SPECT); Magnetic resonance imaging (MRI); Near-infrared fluorescence (NIRF) imaging; Photoacoustic tomography (PAT)
7.  Evidence-Based Novel Changes in Prevalence and Symptom Characteristics of Spleen Deficiency Syndrome in Persons of Varied Health Status and Different Ages: A Cross-Sectional Observational Study 
Deficiency of the organs is a vital pathophysiologic characteristic in the elderly. A core TCM aging theory is known as aging caused by spleen deficiency syndrome (SDS) that can be found in ancient and modern literature. The key objectives of this study were to establish a full-scale trial to evaluate the prevalence, symptom severity, frequency, and distribution of SDS in different age groups as related to health status (healthy, subhealthy, and chronic disease) to elucidate the role of spleen deficiency in the aging process and deterioration of health status. This cross-sectional observational study was conducted in 4 hospitals in China. 1390 participants aged 20–79 were interviewed by investigators who completed questionnaires recording prevalence, severity, and frequency of symptoms as well as other relevant information. The results revealed that prevalence and symptom characteristics of SDS showed regularities with increasing age and deteriorating health status. It supports the TCM concept that spleen deficiency is an important mechanism of aging, subhealth, and chronic diseases. Early recognition of the warning signs and symptoms of SDS may lead to intervention and even prevention strategies for subhealth and chronic diseases as well as promotion of healthy aging.
PMCID: PMC4243480  PMID: 25435892
8.  YAP/TEAD Co-Activator Regulated Pluripotency and Chemoresistance in Ovarian Cancer Initiated Cells 
PLoS ONE  2014;9(11):e109575.
Recent evidence suggests that some solid tumors, including ovarian cancer, contain distinct populations of stem cells that are responsible for tumor initiation, growth, chemo-resistance, and recurrence. The Hippo pathway has attracted considerable attention and some investigators have focused on YAP functions for maintaining stemness and cell differentiation. In this study, we successfully isolated the ovarian cancer initiating cells (OCICs) and demonstrated YAP promoted self-renewal of ovarian cancer initiated cell (OCIC) through its downstream co-activator TEAD. YAP and TEAD families were required for maintaining the expression of specific genes that may be involved in OCICs' stemness and chemoresistance. Taken together, our data first indicate that YAP/TEAD co-activator regulated ovarian cancer initiated cell pluripotency and chemo-resistance. It proposed a new mechanism on the drug resistance in cancer stem cell that Hippo-YAP signal pathway might serve as therapeutic targets for ovarian cancer treatment in clinical.
PMCID: PMC4219672  PMID: 25369529
9.  Image-guided and tumor-targeted drug delivery with radiolabeled unimolecular micelles 
Biomaterials  2013;34(33):8323-8332.
Unimolecular micelles formed by dendritic amphiphilic block copolymers poly(amidoamine)–poly(l-lactide)-b-poly(ethylene glycol) conjugated with anti-CD105 monoclonal antibody (TRC105) and 1,4,7-triazacyclononane-N, N’, N-triacetic acid (NOTA, a macrocyclic chelator for 64Cu) (abbreviated as PAMAM–PLA-b-PEG–TRC105) were synthesized and characterized. Doxorubicin (DOX), a model anti-cancer drug, was loaded into the hydrophobic core of the unimolecular micelles formed by PAMAM and PLA via physical encapsulation. The unimolecular micelles exhibited a uniform size distribution and pH-sensitive drug release behavior. TRC105-conjugated unimolecular micelles showed a CD105-associated cellular uptake in human umbilical vein endothelial cells (HUVEC) compared with non-targeted unimolecular micelles, which was further validated by cellular uptake in CD105-negative MCF-7 cells. In 4T1 murine breast tumor-bearing mice, 64Cu-labeled targeted micelles exhibited a much higher level of tumor accumulation than 64Cu-labeled non-targeted micelles, measured by serial non-invasive positron emission tomography (PET) imaging and confirmed by biodistribution studies. These unimolecular micelles formed by dendritic amphiphilic block copolymers that synergistically integrate passive and active tumor-targeting abilities with pH-controlled drug release and PET imaging capabilities provide the basis for future cancer theranostics.
PMCID: PMC3785312  PMID: 23932288
Unimolecular micelles; Dendritic amphiphilic block copolymer; Nanocarriers; CD105 (endoglin); Molecular imaging; Positron emission tomography (PET)
10.  In Vivo Tumor Targeting and Image-Guided Drug Delivery with Antibody-Conjugated, Radiolabeled Mesoporous Silica Nanoparticles 
ACS nano  2013;7(10):10.1021/nn403617j.
Since the first use of biocompatible mesoporous silica (mSiO2) nanoparticles as drug delivery vehicles, in vivo tumor targeted imaging and enhanced anti-cancer drug delivery has remained a major challenge. In this work, we describe the development of functionalized mSiO2 nanoparticles for actively targeted positron emission tomography (PET) imaging and drug delivery in 4T1 murine breast tumor-bearing mice. Our structural design involves the synthesis, surface functionalization with thiol groups, PEGylation, TRC105 antibody (specific for CD105/endoglin) conjugation, and 64Cu-labeling of uniform 80 nm sized mSiO2 nanoparticles. Systematic in vivo tumor targeting studies clearly demonstrated that 64Cu-NOTA-mSiO2-PEG-TRC105 could accumulate prominently at the 4T1 tumor site via both the enhanced permeability and retention effect and TRC105-mediated binding to tumor vasculature CD105. As a proof-of-concept, we also demonstrated successful enhanced tumor targeted delivery of doxorubicin (DOX) in 4T1 tumor-bearing mice after intravenous injection of DOX-loaded NOTA-mSiO2-PEG-TRC105, which holds great potential for future image-guided drug delivery and targeted cancer therapy.
PMCID: PMC3834886  PMID: 24083623
Mesoporous silica (mSiO2) nanoparticles; tumor angiogenesis; in vivo tumor targeting; positron emission tomography (PET); drug delivery; theranostics
11.  Attenuation of Acetylcholine Activated Potassium Current (IKACh) by Simvastatin, Not Pravastatin in Mouse Atrial Cardiomyocyte: Possible Atrial Fibrillation Preventing Effects of Statin 
PLoS ONE  2014;9(10):e106570.
Statins, 3-hydroxy-3-methyl-glutaryl-CoA reductase inhibitors, are associated with the prevention of atrial fibrillation (AF) by pleiotropic effects. Recent clinical trial studies have demonstrated conflicting results on anti-arrhythmia between lipophilic and hydrophilic statins. However, the underlying mechanisms responsible for anti-arrhythmogenic effects of statins are largely unexplored. In this study, we evaluated the different roles of lipophilic and hydrophilic statins (simvastatin and pravastatin, respectively) in acetylcholine (100 µM)-activated K+ current (IKACh, recorded by nystatin-perforated whole cell patch clamp technique) which are important for AF initiation and maintenance in mouse atrial cardiomyocytes. Our results showed that simvastatin (1–10 µM) inhibited both peak and quasi-steady-state IKACh in a dose-dependent manner. In contrast, pravastatin (10 µM) had no effect on IKACh. Supplementation of substrates for the synthesis of cholesterol (mevalonate, geranylgeranyl pyrophosphate or farnesyl pyrophosphate) did not reverse the effect of simvastatin on IKACh, suggesting a cholesterol-independent effect on IKACh. Furthermore, supplementation of phosphatidylinositol 4,5-bisphosphate, extracellular perfusion of phospholipase C inhibitor or a protein kinase C (PKC) inhibitor had no effect on the inhibitory activity of simvastatin on IKACh. Simvastatin also inhibits adenosine activated IKACh, however, simvastatin does not inhibit IKACh after activated by intracellular loading of GTP gamma S. Importantly, shortening of the action potential duration by acetylcholine was restored by simvastatin but not by pravastatin. Together, these findings demonstrate that lipophilic statins but not hydrophilic statins attenuate IKACh in atrial cardiomyocytes via a mechanism that is independent of cholesterol synthesis or PKC pathway, but may be via the blockade of acetylcholine binding site. Our results may provide important background information for the use of statins in patients with AF.
PMCID: PMC4199526  PMID: 25329899
12.  Diversity of wetland plants used traditionally in China: a literature review 
In comparison with terrestrial plants, those growing in wetlands have been rarely studied ethnobotanically, including in China, yet people living in or near wetlands can accumulate much knowledge of the uses of local wetland plants. A characteristic of wetlands, cutting across climatic zones, is that many species are widely distributed, providing opportunities for studying general patterns of knowledge of the uses of plants across extensive areas, in the present case China. There is urgency in undertaking such studies, given the rapid rates of loss of traditional knowledge of wetland plants as is now occurring.
There have been very few studies specifically on the traditional knowledge of wetland plants in China. However, much information on such knowledge does exist, but dispersed through a wide body of literature that is not specifically ethnobotanical, such as regional Floras. We have undertaken an extensive study of such literature to determine which species of wetland plants have been used traditionally and the main factors influencing patterns shown by such knowledge. Quantitative techniques have been used to evaluate the relative usefulness of different types of wetland plants and regression analyses to determine the extent to which different quantitative indices give similar results.
350 wetland plant species, belonging to 66 families and 187 genera, were found to have been used traditionally in China for a wide range of purposes. The top ten families used, in terms of numbers of species, were Poaceae, Polygonaceae, Cyperaceae, Lamiaceae, Asteraceae, Ranunculaceae, Hydrocharitaceae, Potamogetonaceae, Fabaceae, and Brassicaceae, in total accounting for 58.6% of all species used. These families often dominate wetland vegetation in China. The three most widely used genera were Polygonum, Potamogeton and Cyperus. The main uses of wetlands plants, in terms of numbers of species, were for medicine, food, and forage. Three different ways of assigning an importance value to species (Relative Frequency of Citation RFC; Cultural Importance CI; Cultural Value Index CV) all gave similar results.
A diverse range of wetland plants, in terms of both taxonomic affiliation and type of use, have been used traditionally in China. Medicine, forage and food are the three most important categories of use, the plants providing basic resources used by local people in their everyday lives. Local availability is the main factor influencing which species are used. Quantitative indexes, especially Cultural Value Index, proved very useful for evaluating the usefulness of plants as recorded in the literature.
PMCID: PMC4210556  PMID: 25318542
Wetland plants; Traditional knowledge; Literature study; China
13.  Xiaotan Sanjie decoction attenuates tumor angiogenesis by manipulating Notch-1-regulated proliferation of gastric cancer stem-like cells 
World Journal of Gastroenterology : WJG  2014;20(36):13105-13118.
AIM: To determine the underlying mechanisms of action and influence of Xiaotan Sanjie (XTSJ) decoction on gastric cancer stem-like cells (GCSCs).
METHODS: The gastric cancer cell line MKN-45 line was selected and sorted by FACS using the cancer stem cell marker CD44; the stemness of these cells was checked in our previous study. In an in vitro study, the expression of Notch-1, Hes1, Vascular endothelial growth factor (VEGF), and Ki-67 in both CD44-positive gastric cancer stem-like cells (GCSCs) and CD44-negative cells was measured by Western blot. The effect of XTSJ serum on cell viability and on the above markers was measured by MTT assay and Western blot, respectively. In an in vivo study, the ability to induce angiogenesis and maintenance of GCSCs in CD44-positive-MKN-45- and CD44-negative-engrafted mice were detected by immunohistochemical staining using markers for CD34 and CD44, respectively. The role of XTSJ decoction in regulating the expression of Notch-1, Hes1, VEGF and Ki-67 was measured by Western blot and real-time polymerase chain reaction.
RESULTS: CD44+ GCSCs showed more cell proliferation and VEGF secretion than CD44-negative cells in vitro, which were accompanied by the high expression of Notch-1 and Hes1 and positively associated with tumor growth (GCSCs vs CD44-negative cells, 2.72 ± 0.25 vs 1.46 ± 0.16, P < 0.05) and microvessel density (MVD) (GCSCs vs CD44-negative cells, 8.15 ± 0.42 vs 3.83 ± 0.49, P < 0.001) in vivo. XTSJ decoction inhibited the viability of both cell types in a dose-dependent manner in vitro. Specifically, a significant difference in the medium- (82.87% ± 6.53%) and high-dose XTSJ groups (77.43% ± 7.34%) was detected at 24 h in the CD44+ GCSCs group compared with the saline group (95.42% ± 5.76%) and the low-dose XTSJ group (90.74% ± 6.57%) (P < 0.05). However, the efficacy of XTSJ decoction was reduced in the CD44- groups; significant differences were only detected in the high-dose XTSJ group at 48 h (78.57% ± 6.94%) and 72 h (72.12% ± 7.68%) when compared with the other CD44- groups (P < 0.05). Notably, these differences were highly consistent with the Notch-1, Hes1, VEGF and Ki-67 expression in these cells. Similarly, in vivo, XTSJ decoction inhibited tumor growth in a dose-dependent manner. A significant difference was observed in the medium- (1.76 ± 0.15) and high-dose XTSJ (1.33 ± 0.081) groups compared with the GCSCs control group (2.72 ± 0.25) and the low-dose XTSJ group (2.51 ± 0.25) (P < 0.05). We also detected a remarkable decrease of MVD in the medium- (7.10 ± 0.60) and high-dose XTSJ (5.99 ± 0.47) groups compared with the GCSC control group (8.15 ± 0.42) and the low-dose XTSJ group (8.14 ± 0.46) (P < 0.05). Additionally, CD44 expression was decreased in these groups [medium- (4.43 ± 0.45) and high-dose XTSJ groups (3.56 ± 0.31) vs the GCSC control (5.96 ± 0.46) and low dose XTSJ groups (5.91 ± 0.38)] (P < 0.05). The significant differences in Notch-1, Hes1, VEGF and Ki-67 expression highly mirrored the results of XTSJ decoction in inhibiting tumor growth, MVD and CD44 expression.
CONCLUSION: Notch-1 may play an important role in regulating the proliferation of GCSCs; XTSJ decoction could attenuate tumor angiogenesis, at least partially, by inhibiting Notch-1.
PMCID: PMC4177489  PMID: 25278704
Gastric cancer stem-like cells; Xiaotan Sanjie decoction; Tumor angiogenesis; Notch-1; Vascular endothelial growth factor
14.  Photoacoustic Imaging 
Cold Spring Harbor protocols  2011;2011(9):10.1101/pdb.top065508 pdb.top065508.
Photoacoustic imaging, based on the photoacoustic effect, has come a long way over the last decade. Possessing many attractive characteristics such as the use of non-ionizing electromagnetic waves, good resolution/contrast, portable instrumention, as well as the ability to quantitate the signal to a certain extent, photoacoustic techniques have been applied for the imaging of cancer, wound healing, disorders in the brain, gene expression, among others. As a promising structural, functional and molecular imaging modality for a wide range of biomedical applications, photoacoustic imaging systems can be briefly categorized into two types: photoacoustic tomography (PAT, the focus of this chapter) and photoacoustic microscopy (PAM). We will first briefly describe the endogenous (e.g. hemoglobin and melanin) and exogenous contrast agents (e.g. indocyanine green, various gold nanoparticles, single-walled carbon nanotubes, quantum dots, and fluorescent proteins) for photoacoustic imaging. Next, we will discuss in detail the applications of non-targeted photoacoustic imaging. Recently, molecular photoacoustic (MPA) imaging has gained significant interest and a few proof-of-principle studies have been reported. We will summarize the current state-of-the-art of MPA imaging, including the imaging of gene expression and combination of photoacoustic imaging with other imaging modalities. Lastly, we will point out the obstacles facing photoacoustic imaging. Although photoacoustic imaging will likely continue to be a highly vibrant research field for the years to come, the key question of whether MPA imaging could provide significant advantages over non-targeted photoacoustic imaging remains to be demonstrated in the future.
PMCID: PMC4167744  PMID: 21880823
15.  Detecting Both the Mass and Position of an Accreted Particle by a Micro/Nano-Mechanical Resonator Sensor 
Sensors (Basel, Switzerland)  2014;14(9):16296-16310.
In the application of a micro-/nano-mechanical resonator, the position of an accreted particle and the resonant frequencies are measured by two different physical systems. Detecting the particle position sometimes can be extremely difficult or even impossible, especially when the particle is as small as an atom or a molecule. Using the resonant frequencies to determine the mass and position of an accreted particle formulates an inverse problem. The Dirac delta function and Galerkin method are used to model and formulate an eigenvalue problem of a beam with an accreted particle. An approximate method is proposed by ignoring the off-diagonal elements of the eigenvalue matrix. Based on the approximate method, the mass and position of an accreted particle can be decoupled and uniquely determined by measuring at most three resonant frequencies. The approximate method is demonstrated to be very accurate when the particle mass is small, which is the application scenario for much of the mass sensing of micro-/nano-mechanical resonators. By solving the inverse problem, the position measurement becomes unnecessary, which is of some help to the mass sensing application of a micro-/nano-mechanical resonator by reducing two measurement systems to one. How to apply the method to the general scenario of multiple accreted particles is also discussed.
PMCID: PMC4208176  PMID: 25184493
inverse problem; mass sensing; resonator sensor; resonant frequency; Galerkin method
16.  Transferrin receptor (TfR) trafficking determines brain uptake of TfR antibody affinity variants 
High-affinity transferrin receptor (TfR) bispecific antibodies facilitate trafficking of TfR to lysosomes and induce TfR degradation to decrease the ability of TfR to mediate BBB transcytosis.
Antibodies to transferrin receptor (TfR) have potential use for therapeutic entry into the brain. We have shown that bispecific antibodies against TfR and β-secretase (BACE1 [β-amyloid cleaving enzyme-1]) traverse the blood–brain barrier (BBB) and effectively reduce brain amyloid β levels. We found that optimizing anti-TfR affinity improves brain exposure and BACE1 inhibition. Here we probe the cellular basis of this improvement and explore whether TfR antibody affinity alters the intracellular trafficking of TfR. Comparing high- and low-affinity TfR bispecific antibodies in vivo, we found that high-affinity binding to TfR caused a dose-dependent reduction of brain TfR levels. In vitro live imaging and colocalization experiments revealed that high-affinity TfR bispecific antibodies facilitated the trafficking of TfR to lysosomes and thus induced the degradation of TfR, an observation which was further confirmed in vivo. Importantly, high-affinity anti-TfR dosing induced reductions in brain TfR levels, which significantly decreased brain exposure to a second dose of low-affinity anti-TfR bispecific. Thus, high-affinity anti-TfR alters TfR trafficking, which dramatically impacts the capacity for TfR to mediate BBB transcytosis.
PMCID: PMC3920563  PMID: 24470444
17.  Cannulation of the intradiverticular papilla using a duodenoscope: Is it a safe method? 
World Journal of Gastroenterology : WJG  2014;20(29):10217-10218.
Endoscopic cannulation of the biliary tract is a challenging technique in cases of periampullary diverticula. Many new devices and new manipulations for successful biliary cannulation have been reported. Endoscopy used to locate and cannulate a papilla hidden within a duodenal diverticulum is an effective method. However, the question of which endoscope should be chosen for this procedure, duodenoscope or gastroscope, waits to be answered.
PMCID: PMC4123354  PMID: 25110452
Endoscopic retrograde cholangiopancreatography; Intradiverticular papilla; Cannulation
18.  Automated Synthesis of 18F-Fluoropropoxytryptophan for Amino Acid Transporter System Imaging 
BioMed Research International  2014;2014:492545.
Objective. This study was to develop a cGMP grade of [18F]fluoropropoxytryptophan (18F-FTP) to assess tryptophan transporters using an automated synthesizer. Methods. Tosylpropoxytryptophan (Ts-TP) was reacted with K18F/kryptofix complex. After column purification, solvent evaporation, and hydrolysis, the identity and purity of the product were validated by radio-TLC (1M-ammonium acetate : methanol = 4 : 1) and HPLC (C-18 column, methanol : water = 7 : 3) analyses. In vitro cellular uptake of 18F-FTP and 18F-FDG was performed in human prostate cancer cells. PET imaging studies were performed with 18F-FTP and 18F-FDG in prostate and small cell lung tumor-bearing mice (3.7 MBq/mouse, iv). Results. Radio-TLC and HPLC analyses of 18F-FTP showed that the Rf and Rt values were 0.9 and 9 min, respectively. Radiochemical purity was >99%. The radiochemical yield was 37.7% (EOS 90 min, decay corrected). Cellular uptake of 18F-FTP and 18F-FDG showed enhanced uptake as a function of incubation time. PET imaging studies showed that 18F-FTP had less tumor uptake than 18F-FDG in prostate cancer model. However, 18F-FTP had more uptake than 18F-FDG in small cell lung cancer model. Conclusion. 18F-FTP could be synthesized with high radiochemical yield. Assessment of upregulated transporters activity by 18F-FTP may provide potential applications in differential diagnosis and prediction of early treatment response.
PMCID: PMC4127279  PMID: 25136592
19.  Imaging tumor angiogenesis in breast cancer experimental lung metastasis with positron emission tomography, near-infrared fluorescence, and bioluminescence 
Angiogenesis  2013;16(3):663-674.
The goal of this study was to develop a molecular imaging agent that can allow for both positron emission tomography (PET) and near-infrared fluorescence (NIRF) imaging of CD105 expression in metastatic breast cancer. TRC105, a chimeric anti-CD105 monoclonal antibody, was labeled with both a NIRF dye (i.e., IRDye 800CW) and 64Cu to yield 64Cu-NOTA-TRC105-800CW. Flow cytometry analysis revealed no difference in CD105 binding affinity/specificity between TRC105 and NOTA-TRC105-800CW. Serial bioluminescence imaging (BLI) was carried out to non-invasively monitor the lung tumor burden in BALB/c mice, after intravenous injection of firefly luciferase-transfected 4T1 (i.e., fLuc-4T1) murine breast cancer cells to establish the experimental lung metastasis model. Serial PET imaging revealed that fLuc-4T1 lung tumor uptake of 64Cu-NOTA-TRC105-800CW was 11.9 ± 1.2, 13.9 ± 3.9, and 13.4 ± 2.1 %ID/g at 4, 24, and 48 h post-injection respectively (n = 3). Biodistribution studies, blocking fLuc-4T1 lung tumor uptake with excess TRC105, control experiments with 64Cu-NOTA-cetuximab-800CW (which served as an isotype-matched control), ex vivo BLI/PET/NIRF imaging, autoradiography, and histology all confirmed CD105 specificity of 64Cu-NOTA-TRC105-800CW. Successful PET/NIRF imaging of tumor angiogenesis (i.e., CD105 expression) in the breast cancer experimental lung metastasis model warrants further investigation and clinical translation of dual-labeled TRC105-based agents, which can potentially enable early detection of small metastases and image-guided surgery for tumor removal.
PMCID: PMC3706271  PMID: 23471463
Breast cancer; Tumor angiogenesis; Lung metastasis; Positron emission tomography (PET); Near-infrared fluorescence (NIRF); CD105/endoglin; ImmunoPET; Image-guided surgery
20.  Positron Emission Tomography Imaging of Angiogenesis in a Murine Hindlimb Ischemia Model with 64Cu-Labeled TRC105 
Molecular pharmaceutics  2013;10(7):2749-2756.
The goal of this study was to assess ischemia-induced angiogenesis with 64Cu-NOTA-TRC105 positron emission tomography (PET) in a murine hindlimb ischemia model of peripheral artery disease (PAD). CD105 binding affinity/specificity of NOTA-conjugated TRC105 (an anti-CD105 antibody) was evaluated by flow cytometry, which exhibited no difference from unconjugated TRC105. BALB/c mice were anesthetized and the right femoral artery was ligated to induce hindlimb ischemia, with the left hindlimb serving as an internal control. Laser Doppler imaging showed that perfusion in the ischemic hindlimb plummeted to ~20% of the normal level after surgery, and gradually recovered to near normal level on day 24. Ischemia-induced angiogenesis was non-invasively monitored and quantified with 64Cu-NOTA-TRC105 PET on postoperative days 1, 3, 10, 17, & 24. 64Cu-NOTA-TRC105 uptake in the ischemic hindlimb increased significantly from the control level of 1.6±0.2 %ID/g to 14.1±1.9 %ID/g at day 3 (n=3), and gradually decreased with time (3.4±1.9 %ID/g at day 24), which correlated well with biodistribution studies performed on days 3 & 24. Blocking studies confirmed the CD105 specificity of tracer uptake in the ischemic hindlimb. Increased CD105 expression on days 3 and 10 following ischemia was confirmed by histology and RT-PCR. This is the first report of PET imaging of CD105 expression during ischemia-induced angiogenesis. 64Cu-NOTA-TRC105 PET may play multiple roles in future PAD-related research and improve PAD patient management by identifying the optimal timing of treatment and monitoring the efficacy of therapy.
PMCID: PMC3836864  PMID: 23738915
angiogenesis; ischemia; positron emission tomography (PET); peripheral artery disease (PAD); imaging; CD105 (endoglin)
21.  A 3-year prospective study of the epidemiology of acute respiratory viral infections in hospitalized children in Shenzhen, China 
The epidemiology of local viral etiologies is essential for the management of viral respiratory tract infections. Limited data are available in China to describe the epidemiology of viral respiratory infections, especially in small–medium cities and rural areas.
To determine the viral etiology and seasonality of acute respiratory infections in hospitalized children, a 3-year study was conducted in Shenzhen, China.
Nasopharyngeal aspirates from eligible children were collected. Influenza and other respiratory viruses were tested by molecular assays simultaneously. Data were analyzed to describe the frequency and seasonality.
Of the 2025 children enrolled in the study, 971 (48·0%) were positive for at least one viral pathogen, in which 890 (91·7%) were <4 years of age. The three most prevalent viruses were influenza A (IAV; 35·8%), respiratory syncytial virus (RSV; 30·5%) and human rhinovirus (HRV; 21·5%). Co-infections were found in 302 cases (31·1%), and dual viral infection was dominant. RSV, HRV and IAV were the most frequent viral agents involved in co-infection. On the whole, the obvious seasonal peaks mainly from March to May were observed with peak strength varying from 1 year to another.
This study provides a basic profile of the epidemiology of acute respiratory viral infection in hospitalized children in Shenzhen. The spectrum of viruses in the study site is similar to that in other places, but the seasonality is closely related to geographic position, different from that in big cities in northern China and neighboring Hong Kong.
PMCID: PMC4181804  PMID: 24828783
Acute respiratory tract infection; China; hospitalized children; viruses
22.  MALDI-TOF-MS serum protein profiling for developing diagnostic models and identifying serum markers for discogenic low back pain 
The identification of the cause of chronic low back pain (CLBP) represents a great challenge to orthopedists due to the controversy over the diagnosis of discogenic low back pain (DLBP) and the existence of a number of cases of CLBP of unknown origin. This study aimed to develop diagnostic models to distinguish DLBP from other forms of CLBP and to identify serum biomarkers for DLBP.
Serum samples were collected from patients with DLBP, chronic lumbar disc herniation (LDH), or CLBP of unknown origin, and healthy controls (N), and randomly divided into a training set (n = 30) and a blind test set (n = 30). Matrix-assisted laser desorption ionization time-of-flight mass spectrometry was performed for protein profiling of these samples. After the discriminative ability of two most significantly differential peaks from each two groups was assessed using scatter plots, classification models were developed using differential peptide peaks to evaluate their diagnostic accuracy. The identity of peptides corresponding to three representative differential peaks was analyzed.
The fewest statistically significant differential peaks were identified between DLBP and CLBP (3), followed by CLBP vs. N (5), DLBP vs. N (9), LDH vs. CLBP (20), DLBP vs. LDH (23), and LDH vs. N (43). The discriminative ability of two most significantly differential peaks was poor in classifying DLBP vs. CLBP but good in classifying DLBP vs. LDH. The accuracy of models for classification of DLBP vs. CLBP was not very high in the blind test (forecasting ability, 67.24%; sensitivity, 70%), although a higher accuracy was observed for classification of DLBP vs. LDH and LDH vs. N (forecasting abilities, ~90%; sensitivities, >90%). A further investigation of three representative differential peaks led to the identification of two peaks as peptides of complement C3, and one peak as a human fibrinogen peptide.
Our findings benefit not only the diagnosis of CLBP but also the understanding of the differences between different forms of DLBP. The ability to distinguish between different causes of CLBP and the identification of serum biomarkers may be of great value to diagnose different causes of DLBP and predict treatment efficacy.
PMCID: PMC4061098  PMID: 24889399
Chronic low back pain; Dicogenic low back pain; Lumbar disc herniation; MALDI-TOF-MS; Serum profiling; Biomarker
23.  Role of microstructures on the M1-M2 phase transition in epitaxial VO2 thin films 
Scientific Reports  2014;4:4854.
Vanadium dioxide (VO2) with its unique sharp resistivity change at the metal-insulator transition (MIT) has been extensively considered for the near-future terahertz/infrared devices and energy harvesting systems. Controlling the epitaxial quality and microstructures of vanadium dioxide thin films and understanding the metal-insulator transition behaviors are therefore critical to novel device development. The metal-insulator transition behaviors of the epitaxial vanadium dioxide thin films deposited on Al2O3 (0001) substrates were systematically studied by characterizing the temperature dependency of both Raman spectrum and Fourier transform infrared spectroscopy. Our findings on the correlation between the nucleation dynamics of intermediate monoclinic (M2) phase with microstructures will open a new avenue for the design and integration of advanced heterostructures with controllable multifunctionalities for sensing and imaging system applications.
PMCID: PMC4010922  PMID: 24798056
24.  PET Imaging of CD105/Endoglin Expression with a 61/64Cu-Labeled Fab Antibody Fragment 
The goal of this study was to generate and characterize the Fab fragment of TRC105, a monoclonal antibody that binds with high affinity to human and murine CD105 (i.e. endoglin), and investigate its potential for positron emission tomography (PET) imaging of tumor angiogenesis in a small animal model after 61/64Cu-labeling.
TRC105-Fab was generated by enzymatic papain digestion. The integrity and CD105 binding affinity of TRC105-Fab was evaluated before NOTA (i.e., 1,4,7-triazacyclononane-1,4,7-triacetic acid) conjugation and 61/64Cu-labeling. Serial PET imaging and biodistribution studies were carried out in the syngeneic 4T1 murine breast cancer model to quantify tumor targeting efficacy and normal organ distribution of 61/64Cu-NOTA-TRC105-Fab. Blocking studies with unlabeled TRC105 were performed to confirm CD105 specificity of the tracer in vivo. Immunofluorescence staining was also conducted to correlate tracer uptake in the tumor and normal tissues with CD105 expression.
TRC105-Fab was produced with high purity through papain digestion of TRC105, as confirmed by SDS-PAGE, HPLC analysis, and mass spectrometry. 61/64Cu-labeling of NOTA-TRC105-Fab was achieved with ~50% yield (specific activity: ~44 GBq/µmol). PET imaging revealed rapid uptake of 64Cu-NOTA-TRC105-Fab in the 4T1 tumor (3.6 ± 0.4, 4.2 ± 0.5, 4.9 ± 0.3, 4.4 ± 0.7, and 4.6 ± 0.8 %ID/g at 0.5, 2, 5, 16, and 24 h post-injection respectively; n = 4). Since tumor uptake peaked soon after tracer injection, 61Cu-labeled TRC105-Fab was also able to provide tumor contrast at 3 and 8 h post-injection. CD105 specificity of the tracer was confirmed with blocking studies and histological examination.
Herein we report PET imaging of CD105 expression with 61/64Cu-NOTA-TRC105-Fab, which exhibited prominent and target specific uptake in the 4T1 tumor. The use of a Fab fragment led to much faster tumor uptake (which peaked at a few hours after tracer injection) compared to radiolabeled intact antibody, which may be translated into same day immunoPET imaging for clinical investigation.
PMCID: PMC3625465  PMID: 23344138
Positron emission tomography (PET); Tumor angiogenesis; Antibody fragment; Fab; CD105 (endoglin); 61Cu; 64Cu
25.  Basic Helix-Loop-Helix Transcription Factor Bmsage Is Involved in Regulation of fibroin H-chain Gene via Interaction with SGF1 in Bombyx mori 
PLoS ONE  2014;9(4):e94091.
Silk glands are specialized in the synthesis of several secretory proteins. Expression of genes encoding the silk proteins in Bombyx mori silk glands with strict territorial and developmental specificities is regulated by many transcription factors. In this study, we have characterized B. mori sage, which is closely related to sage in the fruitfly Drosophila melanogaster. It is termed Bmsage; it encodes transcription factor Bmsage, which belongs to the Mesp subfamily, containing a basic helix–loop–helix motif. Bmsage transcripts were detected specifically in the silk glands of B. mori larvae through RT-PCR analysis. Immunoblotting analysis confirmed the Bmsage protein existed exclusively in B. mori middle and posterior silk gland cells. Bmsage has a low level of expression in the 4th instar molting stages, which increases gradually in the 5th instar feeding stages and then declines from the wandering to the pupation stages. Quantitative PCR analysis suggested the expression level of Bmsage in a high silk strain was higher compared to a lower silk strain on day 3 of the larval 5th instar. Furthermore, far western blotting and co-immunoprecipitation assays showed the Bmsage protein interacted with the fork head transcription factor silk gland factor 1 (SGF1). An electrophoretic mobility shift assay showed the complex of Bmsage and SGF1 proteins bound to the A and B elements in the promoter of fibroin H-chain gene(fib-H), respectively. Luciferase reporter gene assays confirmed the complex of Bmsage and SGF1 proteins increased the expression of fib-H. Together, these results suggest Bmsage is involved in the regulation of the expression of fib-H by being together with SGF1 in B. mori PSG cells.
PMCID: PMC3989216  PMID: 24740008

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