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1.  Real-time monitoring of magnetic drug targeting using fibered confocal fluorescence microscopy 
Journal of Controlled Release  2016;244(Pt B):240-246.
Magnetic drug targeting has been proposed as means of concentrating therapeutic agents at a target site and the success of this approach has been demonstrated in a number of studies. However, the behavior of magnetic carriers in blood vessels and tumor microcirculation still remains unclear. In this work, we utilized polymeric magnetic nanocapsules (m-NCs) for magnetic targeting in tumors and dynamically visualized them within blood vessels and tumor tissues before, during and after magnetic field exposure using fibered confocal fluorescence microscopy (FCFM). Our results suggested that the distribution of m-NCs within tumor vasculature changed dramatically, but in a reversible way, upon application and removal of a magnetic field. The m-NCs were concentrated and stayed as clusters near a blood vessel wall when tumors were exposed to a magnetic field but without rupturing the blood vessel. The obtained FCFM images provided in vivo in situ microvascular observations of m-NCs upon magnetic targeting with high spatial resolution but minimally invasive surgical procedures. This proof-of-concept descriptive study in mice is envisaged to track and quantify nanoparticles in vivo in a non-invasive manner at microscopic resolution.
Graphical abstract
Image 1
doi:10.1016/j.jconrel.2016.07.026
PMCID: PMC5176088  PMID: 27449744
Superparamagnetic iron oxide nanoparticles (SPIONs); Magnetic drug targeting; Cellvizio®; Tumor; Nanomedicine
2.  In vitro potency, in vitro and in vivo efficacy of liposomal alendronate in combination with γδ T cell immunotherapy in mice 
Journal of Controlled Release  2016;241:229-241.
Nitrogen-containing bisphosphonates (N-BP), including zoledronic acid (ZOL) and alendronate (ALD), have been proposed as sensitisers in γδ T cell immunotherapy in pre-clinical and clinical studies. Therapeutic efficacy of N-BPs is hampered by their rapid renal excretion and high affinity for bone. Liposomal formulations of N-BP have been proposed to improve accumulation in solid tumours. Liposomal ALD (L-ALD) has been suggested as a suitable alternative to liposomal ZOL (L-ZOL), due to unexpected mice death experienced in pre-clinical studies with the latter. Only one study so far has proven the therapeutic efficacy of L-ALD, in combination with γδ T cell immunotherapy, after intraperitoneal administration of γδ T cell resulting in delayed growth of ovarian cancer in mice. This study aims to assess the in vitro efficacy of L-ALD, in combination with γδ T cell immunotherapy, in a range of cancerous cell lines, using L-ZOL as a comparator. The therapeutic efficacy was tested in a pseudo-metastatic lung mouse model, following intravenous injection of γδ T cell, L-ALD or the combination. In vivo biocompatibility and organ biodistribution studies of L-N-BPs were undertaken simultaneously. Higher concentrations of L-ALD (40–60 μM) than L-ZOL (3–10 μM) were required to produce a comparative reduction in cell viability in vitro, when used in combination with γδ T cells. Significant inhibition of tumour growth was observed after treatment with both L-ALD and γδ T cells in pseudo-metastatic lung melanoma tumour-bearing mice after tail vein injection of both treatments, suggesting that therapeutically relevant concentrations of L-ALD and γδ T cell could be achieved in the tumour sites, resulting in significant delay in tumour growth.
Graphical abstract
Image 1
doi:10.1016/j.jconrel.2016.09.023
PMCID: PMC5073077  PMID: 27664328
Bisphosphonates; γδ T cells; Liposomes; Immunotherapy; Sensitiser
3.  Investigating the effect of tumor vascularization on magnetic targeting in vivo using retrospective design of experiment 
Biomaterials  2016;106:276-285.
Nanocarriers take advantages of the enhanced permeability and retention (EPR) to accumulate passively in solid tumors. Magnetic targeting has shown to further enhance tumor accumulation in response to a magnetic field gradient. It is widely known that passive accumulation of nanocarriers varies hugely in tumor tissues of different tumor vascularization. It is hypothesized that magnetic targeting is likely to be influenced by such factors. In this work, magnetic targeting is assessed in a range of subcutaneously implanted murine tumors, namely, colon (CT26), breast (4T1), lung (Lewis lung carcinoma) cancer and melanoma (B16F10). Passively- and magnetically-driven tumor accumulation of the radiolabeled polymeric magnetic nanocapsules are assessed with gamma counting. The influence of tumor vasculature, namely, the tumor microvessel density, permeability and diameter on passive and magnetic tumor targeting is assessed with the aid of the retrospective design of experiment (DoE) approach. It is clear that the three tumor vascular parameters contribute greatly to both passive and magnetically targeted tumor accumulation but play different roles when nanocarriers are targeted to the tumor with different strategies. It is concluded that tumor permeability is a rate-limiting factor in both targeting modes. Diameter and microvessel density influence passive and magnetic tumor targeting, respectively.
doi:10.1016/j.biomaterials.2016.08.030
PMCID: PMC5027889  PMID: 27573135
Enhanced permeability and retention; Immunohistochemistry; Nanocapsules; Nanomedicine; Superparamagnetic iron oxide nanoparticles
4.  Safety, clinical and immunologic efficacy of a Chinese herbal medicine (FAHF-2) for food allergy 
Background
FAHF-2 is a 9-herb formula based on Traditional Chinese Medicine that blocks peanut anaphylaxis in a murine model. In Phase I studies, FAHF-2 was found to be safe, and well tolerated.
Objective
To evaluate the safety and effectiveness of FAHF-2 as a treatment for food allergy.
Methods
In this double-blind, randomized, placebo-controlled study, 68 subjects, 12-45 years of age, with allergies to peanut, tree nut, sesame, fish, and/or shellfish, confirmed by baseline double-blind, placebo controlled food challenge (DBPCFC), received FAHF-2 (n=46) or placebo (n=22). After 6 months of therapy, subjects underwent DBPCFC. For those who demonstrated increases in eliciting dose, a repeat DBPCFC was performed 3 months after stopping therapy.
Results
Treatment was well-tolerated with no serious adverse events. By intent-to-treat analysis, the placebo group had a higher eliciting dose and cumulative dose (p=0.05) at the end of treatment DBPCFC. There was no difference in the requirement for epinephrine to treat reactions (p=0.55). There were no significant differences in allergen-specific IgE and IgG4, cytokine production by PBMCs or basophil activation between active and placebo groups. In vitro immunological studies performed on subject baseline PBMCs incubated with FAHF-2 and food allergen produced significantly less IL-5, greater IL-10 and increased numbers of Tregs than untreated cells. Notably, 44% of subjects had poor drug adherence for at least one-third of the study period.
Conclusion
FAHF-2 is a safe herbal medication for food allergic individuals and shows favorable in vitro immunomodulatory effects; however, efficacy for improving tolerance to food allergens is not demonstrated at the dose and duration used.
doi:10.1016/j.jaci.2015.04.029
PMCID: PMC4600418  PMID: 26044855
food allergy; FAHF-2; Chinese herbal therapy; peanut allergy
5.  Wearable Sensor/Device (Fitbit One) and SMS Text-Messaging Prompts to Increase Physical Activity in Overweight and Obese Adults: A Randomized Controlled Trial 
Telemedicine Journal and e-Health  2015;21(10):782-792.
Abstract
Background: Studies have shown self-monitoring can modify health behaviors, including physical activity (PA). This study tested the utility of a wearable sensor/device (Fitbit® One™; Fitbit Inc., San Francisco, CA) and short message service (SMS) text-messaging prompts to increase PA in overweight and obese adults. Materials and Methods: Sixty-seven adults wore a Fitbit One tracker for 6 weeks; half were randomized to also receive three daily SMS-based PA prompts. The Fitbit One consisted of a wearable tracker for instant feedback on performance and a Web site/mobile application (app) for detailed summaries. Outcome measures were objectively measured steps and minutes of PA by intensity using two accelerometers: Actigraph™ (Pensacola, FL) GT3X+ (primary measure) at baseline and Week 6 and Fitbit One (secondary measure) at baseline and Weeks 1, 2, 3, 4, 5, and 6. Results: Mixed-model repeated-measures analysis of primary measures indicated a significant within-group increase of +4.3 (standard error [SE]=2.0) min/week of moderate- to vigorous-intensity PA (MVPA) at 6-week follow-up (p=0.04) in the comparison group (Fitbit only), but no study group differences across PA levels. Secondary measures indicated the SMS text-messaging effect lasted for only 1 week: the intervention group increased by +1,266 steps (SE=491; p=0.01), +17.8 min/week MVPA (SE=8.5; p=0.04), and +38.3 min/week total PA (SE=15.9; p=0.02) compared with no changes in the comparison group, and these between-group differences were significant for steps (p=0.01), fairly/very active minutes (p<0.01), and total active minutes (p=0.02). Conclusions: These data suggest that the Fitbit One achieved a small increase in MVPA at follow-up and that the SMS-based PA prompts were insufficient in increasing PA beyond 1 week. Future studies can test this intervention in those requiring less help and/or test strategies to increase participants' engagement levels.
doi:10.1089/tmj.2014.0176
PMCID: PMC4842945  PMID: 26431257
behavioral health; e-health; mobile health; sensor technology; technology
6.  Dual stimulation of antigen presenting cells using carbon nanotube-based vaccine delivery system for cancer immunotherapy 
Biomaterials  2016;104:310-322.
Although anti−cancer immuno−based combinatorial therapeutic approaches have shown promising results, efficient tumour eradication demands further intensification of anti−tumour immune response. With the emerging field of nanovaccinology, multi−walled carbon nanotubes (MWNTs) have manifested prominent potentials as tumour antigen nanocarriers. Nevertheless, the utilization of MWNTs in co−delivering antigen along with different types of immunoadjuvants to antigen presenting cells (APCs) has not been investigated yet. We hypothesized that harnessing MWNT for concurrent delivery of cytosine−phosphate−guanine oligodeoxynucleotide (CpG) and anti-CD40 Ig (αCD40), as immunoadjuvants, along with the model antigen ovalbumin (OVA) could potentiate immune response induced against OVA−expressing tumour cells. We initially investigated the effective method to co−deliver OVA and CpG using MWNT to the APC. Covalent conjugation of OVA and CpG prior to loading onto MWNTs markedly augmented the CpG−mediated adjuvanticity, as demonstrated by the significantly increased OVA−specific T cell responses in vitro and in C57BL/6 mice. αCD40 was then included as a second immunoadjuvant to further intensify the immune response. Immune response elicited in vitro and in vivo by OVA, CpG and αCD40 was significantly potentiated by their co−incorporation onto the MWNTs. Furthermore, MWNT remarkably improved the ability of co−loaded OVA, CpG and αCD40 in inhibiting the growth of OVA−expressing B16F10 melanoma cells in subcutaneous or lung pseudo−metastatic tumour models. Therefore, this study suggests that the utilization of MWNTs for the co−delivery of tumour−derived antigen, CpG and αCD40 could be a competent approach for efficient tumours eradication.
doi:10.1016/j.biomaterials.2016.07.005
PMCID: PMC4993816  PMID: 27475727
Carbon nanotubes; Dendritic cells; Nanomedicine; Vaccine delivery; Cancer vaccines
7.  Effect of educational and electronic medical record interventions on food allergy management 
Allergy and Asthma Proceedings  2016;37(5):404-408.
Background:
The growing prevalence of food allergies indicates a responsibility among primary care providers to ensure that their patients receive accurate diagnosis and management.
Objective:
To improve physician knowledge and management of food allergies by implementing educational and electronic medical record interventions.
Methods:
Pre- and posttest scores of pediatric residents and faculty were analyzed to assess the effectiveness of an educational session designed to improve knowledge of food allergy management. One year later, a best practice advisory was implemented in the electronic medical record to alert providers to consider allergy referral whenever a diagnosis code for food allergy or epinephrine autoinjector prescription was entered. A review of charts 6 months before and 6 months after each intervention was completed to determine the impact of both interventions. Outcome measurements included referrals to an allergy clinic, prescription of self-injectable epinephrine, and documentation that written emergency action plans were provided.
Results:
There was a significant increase in test scores immediately after the educational intervention (mean, 56.2 versus 84.3%; p < 0.001). Posttest scores remained significantly higher than preintervention scores 6 months later (mean score, 68.0 versus 56.2%; p = 0.006). Although knowledge improved, there was no significant difference in the percentage of patients who were provided allergy referral, were prescribed an epinephrine autoinjector, or were given an emergency action plan before and after both interventions.
Conclusion:
Neither intervention resulted in improvements in the management of children with food allergies at our pediatrics clinic. Further studies are needed to identify effective strategies to improve management of food allergies by primary care physicians.
doi:10.2500/aap.2016.37.3970
PMCID: PMC5013233  PMID: 27657525
Food allergy; quality improvement; primary care; medical education; electronic medical record
8.  E-cigarette Marketing and Older Smokers: Road to Renormalization 
Objectives
To describe older smokers’ perceptions of risks and use of e-cigarettes, and their responses to marketing and knowledge of, and opinions about, regulation of e-cigarettes.
Methods
Eight 90-minute focus groups with 8 to 9 participants met in urban and suburban California to discuss topics related to cigarettes and alternative tobacco products.
Results
Older adults are using e-cigarettes for cessation and as a way to circumvent no-smoking policies; they have false perceptions about the effectiveness and safety of e-cigarettes. They perceive e-cigarette marketing as a way to renormalize smoking.
Conclusions
To stem the current epidemic of nicotine addiction, the FDA must take immediate action because e-cigarette advertising promotes dual use and may contribute to the renormalization of smoking.
doi:10.5993/AJHB.39.3.9
PMCID: PMC4351761  PMID: 25741681
older smokers; e-cigarettes; marketing; perception; use
9.  Epinephrine Use in Positive Oral Food Challenges Performed as Screening Test for Food Allergy Therapy Trials 
Background
Previous studies report epinephrine use for positive oral food challenges (OFCs) to be 9–11% when generally performed to determine outgrowth of food allergies. Epinephrine use for positive OFCs performed as screening criteria for enrollment in therapeutic trials for food allergy has not been reported.
Objective
To assess the characteristics and treatment for positive OFCs performed for screening subjects for food therapeutic trials.
Methods
Retrospective review of positive screening OFCs from two treatment trials, Food Allergy Herbal Formula-2 (FAHF-2) (n=45) and Milk Oral Immunotherapy (MOIT) (n=29) conducted at the Icahn School of Medicine at Mount Sinai was performed.
Results
The most common initial symptom elicited was oral pruritus, reported for 81% (n=60) of subjects. Overall, subjective gastrointestinal symptoms (oral pruritus, throat pruritus, nausea, abdominal pain) were most common (97.3% subjects), followed by cutaneous symptoms (48.7%). Of the 74 positive DBPCFCs, 29 (39.2%) were treated with epinephrine; 2 of these subjects received 2 doses of epinephrine (6.9% of the reactions treated with epinephrine or 2.7% of all reactions). Biphasic reactions were infrequent, occurring in 3 subjects (4%).
Conclusions
Screening OFCs to confirm food allergies can be performed safely, but there was a higher rate of epinephrine use compared to OFCs used for assessing food allergy outgrowth. Therefore, personnel skilled and experienced in the recognition of early signs and symptoms of anaphylaxis who can promptly initiate treatment are required.
doi:10.1016/j.jaip.2014.10.008
PMCID: PMC4426243  PMID: 25609353
Epinephrine; positive oral food challenge; anaphylaxis; food allergy
10.  Effect of environmental allergen sensitization on asthma morbidity in inner city asthmatic children 
Background
Asthma causes significant morbidity in children, and studies have demonstrated that environmental allergies contribute to increased asthma morbidity.
Objective
We investigated the differences between allergen skin tests and specific IgE and the role of IgG in regards to allergen exposure levels, and asthma morbidity in inner-city children.
Methods
Five hundred and six serum samples from the National Cooperative Inner City Asthma Study (NCICAS) were evaluated for specific IgE to cockroach (Blattella germanica), dust mite (Dermatophagoides farinae) and Alternaria as well as specific IgG and IgG4 to cockroach (B. germanica) and total IgE levels. Associations between sensitization to these allergens, exposures, and asthma morbidity were determined.
Results
Sensitization to environmental allergens and total IgE correlated with increased healthcare and medication use, but not with wheeze symptoms. Sensitization with exposure to cockroach was associated with increased asthma morbidity, whereas dust mite sensitization was correlated with asthma morbidity independent of exposure. There was also a strong correlation between specific IgE levels and skin test results, but the tests did not always agree. The relationship between specific IgE and asthma morbidity is linear with no obvious cutoff value. Increased Bla g 1 in the home was a good predictor for sensitization; however this relationship was not demonstrated for Der f 1. Cockroach-specific IgG correlated with increased healthcare use, however, there was no modifying effect of specific IgG or IgG4 on the association between cockroach-specific IgE and asthma morbidity.
Conclusions
Specific IgE levels and prick skin test results to environmental allergens can serve as markers of severe asthma for inner-city children. Asthma morbidity increased in a linear manner with specific IgE levels. Cockroach-specific IgG was not an important predictor or modifier of asthma morbidity.
doi:10.1111/j.1365-2222.2009.03225.x
PMCID: PMC4785875  PMID: 19489919
Alternaria; asthma; cockroach; dust mite; sensitization
11.  Carbon nanotubes' surface chemistry determines their potency as vaccine nanocarriers in vitro and in vivo 
Journal of Controlled Release  2016;225:205-216.
Carbon nanotubes (CNTs) have shown marked capabilities in enhancing antigen delivery to antigen presenting cells. However, proper understanding of how altering the physical properties of CNTs may influence antigen uptake by antigen presenting cells, such as dendritic cells (DCs), has not been established yet. We hypothesized that altering the physical properties of multi-walled CNTs (MWNTs)-antigen conjugates, e.g. length and surface charge, can affect the internalization of MWNT-antigen by DCs, hence the induced immune response potency. For this purpose, pristine MWNTs (p-MWNTs) were exposed to various chemical reactions to modify their physical properties then conjugated to ovalbumin (OVA), a model antigen. The yielded MWNTs-OVA conjugates were long MWNT-OVA (~ 386 nm), bearing net positive charge (5.8 mV), or short MWNTs-OVA (~ 122 nm) of increasing negative charges (− 23.4, − 35.8 or − 39 mV). Compared to the short MWNTs-OVA bearing high negative charges, short MWNT-OVA with the lowest negative charge demonstrated better cellular uptake and OVA-specific immune response both in vitro and in vivo. However, long positively-charged MWNT-OVA showed limited cellular uptake and OVA specific immune response in contrast to short MWNT-OVA displaying the least negative charge. We suggest that reduction in charge negativity of MWNT-antigen conjugate enhances cellular uptake and thus the elicited immune response intensity. Nevertheless, length of MWNT-antigen conjugate might also affect the cellular uptake and immune response potency; highlighting the importance of physical properties as a consideration in designing a MWNT-based vaccine delivery system.
Graphical abstract
doi:10.1016/j.jconrel.2016.01.030
PMCID: PMC4778609  PMID: 26802552
Vaccine delivery; Carbon nanotubes; Dendritic cells; Nanomedicine
12.  Translocation of LRP1 targeted carbon nanotubes of different diameters across the blood–brain barrier in vitro and in vivo 
Journal of Controlled Release  2016;225:217-229.
Brain glioblastoma and neurodegenerative diseases are still largely untreated due to the inability of most drugs to cross the blood–brain barrier (BBB). Nanoparticles have emerged as promising tools for drug delivery applications to the brain; in particular carbon nanotubes (CNTs) that have shown an intrinsic ability to cross the BBB in vitro and in vivo. Angiopep-2 (ANG), a ligand for the low-density lipoprotein receptor-related protein-1 (LRP1), has also shown promising results as a targeting ligand for brain delivery using nanoparticles (NPs). Here, we investigate the ability of ANG-targeted chemically-functionalised multi-walled carbon nanotubes (f-MWNTs) to cross the BBB in vitro and in vivo. ANG was conjugated to wide and thin f-MWNTs creating w-MWNT-ANG and t-MWNT-ANG, respectively. All f-MWNTs were radiolabelled to facilitate quantitative analyses by γ-scintigraphy. ANG conjugation to f-MWNTs enhanced BBB transport of w- and t-MWNTs-ANG compared to their non-targeted equivalents using an in vitro co-cultured BBB model consisting of primary porcine brain endothelial cells (PBEC) and primary rat astrocytes. Additionally, following intravenous administration w-MWNTs-ANG showed significantly higher whole brain uptake than the non-targeted w-MWNT in vivo reaching ~ 2% injected dose per g of brain (%ID/g) within the first hour post-injection. Furthermore, using a syngeneic glioma model, w-MWNT-ANG showed enhanced uptake in glioma brain compared to normal brain at 24 h post-injection. t-MWNTs-ANG, on the other hand, showed higher brain accumulation than w-MWNTs. However, no significant differences were observed between t-MWNT and t-MWNT-ANG indicating the importance of f-MWNTs diameter towards their brain accumulation. The inherent brain accumulation ability of f-MWNTs coupled with improved brain-targeting by ANG favours the future clinical applications of f-MWNT-ANG to deliver active therapeutics for brain glioma therapy.
Graphical abstract
doi:10.1016/j.jconrel.2016.01.031
PMCID: PMC4778610  PMID: 26809004
Nanomedicine; Targeting; Transcytosis; Angiopep-2; Brain delivery; Carbon nanotube
13.  Kinetics of functionalised carbon nanotube distribution in mouse brain after systemic injection: Spatial to ultra-structural analyses 
Earlier studies proved the success of using chemically functionalised multi-walled carbon nanotubes (f-MWNTs) as nanocarriers to the brain. Little insight into the kinetics of brain distribution of f-MWNTs in vivo has been reported. This study employed a wide range of qualitative and quantitative techniques with the aim of shedding the light on f-MWNT's brain distribution following intravenous injection. γ-Scintigraphy quantified the uptake of studied radiolabelled f-MWNT in the whole brain parenchyma and capillaries while 3D-single photon emission computed tomography/computed tomography imaging and autoradiography illustrated spatial distribution within various brain regions. Raman and multiphoton luminescence together with transmission electron microscopy confirmed the presence of intact f-MWNT in mouse brain, in a label-free manner. The results evidenced the presence of f-MWNT in mice brain parenchyma, in addition to brain endothelium. Such information on the rate and extent of regional and cellular brain distribution is needed before further implementation into neurological therapeutics can be made.
Graphical abstract
doi:10.1016/j.jconrel.2015.12.039
PMCID: PMC4756275  PMID: 26742944
Carbon nanotubes; Brain drug delivery; Blood–brain barrier; Nanomedicine; SPECT/CT imaging; Multi-photon luminescence microscopy
14.  Improving the identification of priority populations to increase hepatitis B testing rates, 2012 
BMC Public Health  2016;16:95.
Background
It is estimated that over 40 % of the 218,000 people with chronic hepatitis B (CHB) in Australia in 2011 are undiagnosed. A disproportionate number of those with undiagnosed infection were born in the Asia-Pacific region. Undiagnosed CHB can lead to ongoing transmission and late diagnosis limits opportunities to prevent progression to hepatocellular carcinoma (HCC) and cirrhosis.
Strategies are needed to increase testing for hepatitis B virus (HBV) (including culturally and linguistically diverse communities, Aboriginal and/or Torres Strait Islander (Indigenous) people and people who inject drugs). General practitioners (GPs) have a vital role in increasing HBV testing and the timely diagnosis CHB. This paper describes the impact of a GP-based screening intervention to improve CHB diagnosis among priority populations in Melbourne, Australia.
Methods
A non-randomised, pre-post intervention study was conducted between 2012 and 2013 with three general practices in Melbourne, Australia. Using clinic electronic health records three priority populations known to be at increased CHB risk in Australia (1: Asian-born patients or patients of Asian ethnicity living in Australia; 2: Indigenous people; or 3): people with a history of injecting drugs were identified and their HBV status recorded. A random sample were then invited to attend their GP for HBV testing and/or vaccination. Baseline and follow-up electronic data collection identified patients that subsequently had a consultation and HBV screening test and/or vaccination.
Results
From a total of 33,297 active patients, 2674 (8 %) were identified as a priority population at baseline; 2275 (85.1 %) of these patients had unknown HBV status from which 338 (14.0 %) were randomly sampled. One-fifth (n = 73, 21.6 %) of sampled patients subsequently had a GP consultation during the study period; only four people (5.5 %) were subsequently tested for HBV (CHB detected in n = 1) and none were vaccinated against HBV.
Conclusion
CHB infection is an important long-term health issue in Australia and strategies to increase appropriate and timely testing are required. The study was effective at identifying whether Asian-born patients and patients of Asian had been tested or vaccinated for HBV; however the intervention was not effective at increasing HBV testing.
doi:10.1186/s12889-016-2716-7
PMCID: PMC4735953  PMID: 26832144
Hepatitis B; Prevention & control; Asian continental ancestry group; Electronic health records
15.  Triple-Modal Imaging of Magnetically-Targeted Nanocapsules in Solid Tumours In Vivo 
Theranostics  2016;6(3):342-356.
Triple-modal imaging magnetic nanocapsules, encapsulating hydrophobic superparamagnetic iron oxide nanoparticles, are formulated and used to magnetically target solid tumours after intravenous administration in tumour-bearing mice. The engineered magnetic polymeric nanocapsules m-NCs are ~200 nm in size with negative Zeta potential and shown to be spherical in shape. The loading efficiency of superparamagnetic iron oxide nanoparticles in the m-NC was ~100%. Up to ~3- and ~2.2-fold increase in tumour uptake at 1 and 24 h was achieved, when a static magnetic field was applied to the tumour for 1 hour. m-NCs, with multiple imaging probes (e.g. indocyanine green, superparamagnetic iron oxide nanoparticles and indium-111), were capable of triple-modal imaging (fluorescence/magnetic resonance/nuclear imaging) in vivo. Using triple-modal imaging is to overcome the intrinsic limitations of single modality imaging and provides complementary information on the spatial distribution of the nanocarrier within the tumour. The significant findings of this study could open up new research perspectives in using novel magnetically-responsive nanomaterials in magnetic-drug targeting combined with multi-modal imaging.
doi:10.7150/thno.11918
PMCID: PMC4737722  PMID: 26909110
PEGylated PLGA; magnetic targeting; optical imaging; nuclear imaging; magnetic resonance imaging
16.  Passively Targeted Curcumin-Loaded PEGylated PLGA Nanocapsules for Colon Cancer Therapy In Vivo 
Clinical applications of curcumin for the treatment of cancer and other chronic diseases have been mainly hindered by its short biological half-life and poor water solubility. Nanotechnology-based drug delivery systems have the potential to enhance the efficacy of poorly soluble drugs for systemic delivery. This study proposes the use of poly(lactic-co-glycolic acid) (PLGA)-based polymeric oil-cored nanocapsules (NCs) for curcumin loading and delivery to colon cancer in mice after systemic injection. Formulations of different oil compositions are prepared and characterized for their curcumin loading, physico-chemical properties, and shelf-life stability. The results indicate that castor oil-cored PLGA-based NC achieves high drug loading efficiency (≈18% w(drug)/w(polymer)%) compared to previously reported NCs. Curcumin-loaded NCs internalize more efficiently in CT26 cells than the free drug, and exert therapeutic activity in vitro, leading to apoptosis and blocking the cell cycle. In addition, the formulated NC exhibits an extended blood circulation profile compared to the non-PEGylated NC, and accumulates in the subcutaneous CT26-tumors in mice, after systemic administration. The results are confirmed by optical and single photon emission computed tomography/computed tomography (SPECT/CT) imaging. In vivo growth delay studies are performed, and significantly smaller tumor volumes are achieved compared to empty NC injected animals. This study shows the great potential of the formulated NC for treating colon cancer.
doi:10.1002/smll.201403799
PMCID: PMC4660879  PMID: 26140363
anticancer therapy; CT26 cells; hydrophobic-drugs; oil-core; single photon emission computed tomography/computed tomography (SPECT/CT); tumors
17.  International survey of knowledge of food-induced anaphylaxis 
Background
Studies show that anaphylaxis is under-recognized and epinephrine (adrenaline) is under-used by medical personnel as well as patients and their families. This study assesses the knowledge of food-induced anaphylaxis diagnosis and management across different populations of providers and caregivers and other interested respondents.
Methods
An online survey embedded in a case discussion food-induced anaphylaxis was distributed by Medscape to registered members.
Results
7822 responders who started the activity chose to answer at least some of the questions presented (response rate 39.5%). Over 80% of responders in all groups correctly identified the case of anaphylaxis with prominent skin and respiratory symptoms, however, only 55% correctly recognized the case without skin symptoms as anaphylaxis. Only 23% of responders correctly selected risk factors for anaphylaxis, with physicians significantly more likely to choose the correct answers as compared to allied health, other health professionals and medical students (p<0.001). Ninety five perecnt selected epinephrine (adrenaline) as the most appropriate treatment for anaphylaxis, and 81% correctly indicated that there are no absolute contraindications for epinephrine (adrenaline) in the setting of anaphylaxis. When presented a case of a child with no documented history of allergies who has symptoms of anaphylaxis, more physicians than any other group chose to administer stock epinephrine (adrenaline) (73% vs 60%, p<0.001).
Conclusion
Specific knowledge deficits for food-induced anaphylaxis persist across all groups. Further educational efforts should be aimed not only at the medical community but also for the entire caregiver community and general public, to optimize care for food allergic individuals.
doi:10.1111/pai.12284
PMCID: PMC4302004  PMID: 25263184
allergy; anaphylaxis; epinephrine (adrenaline); food
19.  Solvent-Free Click-Mechanochemistry for the Preparation of Cancer Cell Targeting Graphene Oxide 
ACS Applied Materials & Interfaces  2015;7(34):18920-18923.
Polyethylene glycol-functionalized nanographene oxide (PEGylated n-GO) was synthesized from alkyne-modified n-GO, using solvent-free click-mechanochemistry, i.e., copper(I)-catalyzed azide–alkyne cycloaddition (CuAAC). The modified n-GO was subsequently conjugated to a mucin 1 receptor immunoglobulin G antibody (anti-MUC1 IgG) via thiol–ene coupling reaction. n-GO derivatives were characterized with Fourier-transformed infrared (FT-IR) spectroscopy, thermogravimetric analysis (TGA), Bradford assay, sodium dodecyl sulfate polyacrylamide gel electrophoresis (SDS-PAGE), and atomic force microscopy (AFM). Cell targeting was confirmed in vitro in MDA-MB-231 cells, either expressing or lacking MUC1 receptors, using flow cytometry, confocal laser scanning microscopy (CLSM) and multiphoton (MP) fluorescence microscopy. Biocompatibility was assessed using the modified lactate dehydrongenase (mLDH) assay.
doi:10.1021/acsami.5b06250
PMCID: PMC4559840  PMID: 26278410
antibody; nanomedicine; drug delivery; toxicity; breast cancer
20.  Winter birth in inner city asthmatic children is associated with increased food allergen sensitization risk 
doi:10.1016/j.jaci.2014.05.002
PMCID: PMC4119828  PMID: 24954275
asthma; vitamin D; food allergy; peanut; milk; egg; wheat; soy; inner city
21.  Serum IgE and risk of pancreatic cancer in the Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial (PLCO) 
Epidemiologic studies have consistently found that self-reported allergies are associated with reduced risk of pancreatic cancer. Our aim was to prospectively assess the relationship between serum IgE, a marker of allergy, and risk. This nested case-control study within the Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial (PLCO) included subjects enrolled in 1994-2001 and followed through 2010. There were 283 cases of pancreatic cancer and 544 controls matched on age, gender, race, and calendar date of blood draw. Using the ImmunoCAP system, we measured total IgE (normal, borderline, elevated), IgE to respiratory allergens, and IgE to food allergens (negative or positive) in serum collected at baseline. Odds ratios (OR) and 95% confidence intervals (CI) were estimated using conditional logistic regression. We assessed interactions with age, gender, smoking, body mass index, and time between randomization and case diagnosis. Overall, there was no association between the IgE measures and risk. We found a statistically significant interaction by baseline age: in those aged >65, elevated risks were observed for borderline total IgE (OR=1.43; 95% CI, 0.88-2.32) and elevated total IgE (OR=1.98; 95% CI, 1.16-3.37) and positive IgE to food allergens (OR=2.83; 95% CI, 1.29-6.20); among participants <65, ORs were <1. Other interactions were not statistically significant. The reduced risk of pancreatic cancer associated with self-reported allergies is not reflected in serum IgE.
doi:10.1158/1055-9965.EPI-13-1359
PMCID: PMC4120187  PMID: 24718282
pancreatic cancer; allergies; IgE; biomarkers
22.  Baseline Depressive Symptoms, Completion of Study Assessments, and Behavior Change in a Long-Term Dietary Intervention Among Breast Cancer Survivors 
Annals of Behavioral Medicine  2015;49(6):819-827.
Background
Depressive symptoms can lower adherence and change in dietary studies. Behavioral activation may reduce these effects.
Purpose
This study aims to assess relationships among depressive symptoms on adherence and dietary change in the Women’s Healthy Eating and Living (WHEL) Study
Methods
Secondary analyses from the WHEL Study, which achieved major dietary change in breast cancer survivors (N = 2817), were conducted. Logistic regressions were undertaken of baseline depressive symptoms (six-item Center for Epidemiologic Studies Depression Scale (CES-D)) with (1) completion of 1- and 4-year study assessments and (2) validated change in dietary behavior in the intervention group.
Results
In the comparison group (vs. intervention), depressive symptoms lowered completion of dietary recalls and clinic visits [4 years: odds ratio (OR) = 2.0; 95 % confidence interval (CI) = 1.4–3.0]. The behaviorally oriented intervention achieved major change in those furthest from study targets, although changes were lower in those with depressive symptoms: fruit/vegetable (+37.2 %), fiber (+49.0 %), and fat (−22.4 %).
Conclusions
Behavioral activation in dietary change interventions can overcome the impact of depressive symptoms.
doi:10.1007/s12160-015-9716-1
PMCID: PMC4633436  PMID: 26091977
Dietary change; Depressive symptoms; Adherence; Behavioral activation
23.  Magnetically Decorated Multi-Walled Carbon Nanotubes as Dual MRI and SPECT Contrast Agents 
Advanced functional materials  2014;24(13):1880-1894.
Carbon nanotubes (CNTs) have been proposed as one of the most promising nanomaterials to be used in biomedicine for their applications in drug/gene delivery as well as biomedical imaging. The present study developed radio-labeled iron oxide decorated multi-walled CNTs (MWNT) as dual magnetic resonance (MR) and single photon emission computed tomography (SPECT) imaging agents. Hybrids containing different amounts of iron oxide were synthesized by in situ generation. Physicochemical characterisations revealed the presence of superparamagnetic iron oxide nanoparticles (SPION) granted the magnetic properties of the hybrids. Further comprehensive examinations including high resolution transmission electron microscopy (HRTEM), fast Fourier transform simulations (FFT), X-ray diffraction (XRD) and X-ray photoelectron spectroscopy (XPS) assured the conformation of prepared SPION as γ-Fe2O3. High r2 relaxivities were obtained in both phantom and in vivo MRI compared to the clinically approved SPION Endorem®. The hybrids were successfully radio-labeled with technetium-99m through a functionalized bisphosphonate and enabled SPECT/CT imaging and γ-scintigraphy to quantitatively analyze the biodistribution in mice. No abnormality was found by histological examination and the presence of SPION and MWNT were identified by Perls stain and Neutral Red stain, respectively. TEM images of liver and spleen tissues showed the co-localization of SPION and MWNT within the same intracellular vesicles, indicating the in vivo stability of the hybrids after intravenous injection. The results demonstrated the capability of the present SPION-MWNT hybrids as dual MRI and SPECT contrast agents for in vivo use.
Graphic abstract
Dual SPECT and MR imaging of SPION-MWNT hybrids phantoms
Fe2O3-MWNT hybrids were dispersed in 1% Pluronic® F-127 solution and imaged by MR or SPECT/CT
doi:10.1002/adfm.201302892
PMCID: PMC4471136  PMID: 26097444
carbon nanotubes; magnetic nanoparticles; MRI; SPECT; dual imaging
24.  Cationic Liposome- Multi-Walled Carbon Nanotubes Hybrids for Dual siPLK1 and Doxorubicin Delivery In Vitro 
Pharmaceutical Research  2015;32(10):3293-3308.
Purpose
To formulate f-MWNTs-cationic liposome hybrids for the simultaneous delivery of siPLK1 and doxorubicin to cancer cells.
Method
f-MWNTs-cationic liposome hybrids were prepared by the thin film hydration method where the lipid film was hydrated with 100 μg/ml or 1 mg/ml of ox-MWNTs-NH3+ or MWNTs-NH3+ in 5% dextrose. siRNA complexation and protection ability was determined by agarose gel electrophoresis. f-MWNTs and liposome interaction was evaluated using Nile Red (NR) fluorescence spectroscopy. Cellular uptake in A549 cells was assessed by flow cytometry. Silencing of target proteins was determined by Luciferase and MTT assays. Sub-G1 analysis was performed to evaluate apoptosis following co-delivery of siPLK1 and Doxorubicin (Dox).
Results
Zeta potential and siRNA complexation profile obtained for all hybrids were comparable to those achieved with cationic liposomes. ox-MWNTs-NH3+ showed greater extent of interaction with cationic liposomes compared to MWNTs-NH3+. ox-MWNTs-NH3+ was able to protect siRNA from nuclease-mediated degradation. Enhanced cellular uptake of both the carrier and loaded siRNA in A549 cell, were observed for this hybrid compared to the liposomal carrier. A synergistic pro-apoptotic effect was obtained when siPLK1 silencing was combined with doxorubicin treatment for the hybrid:siRNA complexes compared to the lipoplexes, in A549 cells in vitro.
Conclusions
f-MWNTs-cationic liposome hybrid designed in this study can serve as a potential vehicle for the co-delivery of siRNA and cytotoxic drugs to cancer cells in vitro.
Electronic supplementary material
The online version of this article (doi:10.1007/s11095-015-1707-1) contains supplementary material, which is available to authorized users.
doi:10.1007/s11095-015-1707-1
PMCID: PMC4577551  PMID: 26085038
A549; cancer cells; gene silencing; multi-walled carbon nanotubes; siRNA

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