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1.  Use of a nanoporous biodegradable miniature device to regulate cytokine release for cancer treatment 
The clinical management of locally recurrent or unresectable malignant melanoma continues to pose a significant challenge. These lesions are typically painful and currently available treatments, such as repeated intratumoral injections of interferon-alpha (IFN-α), are costly and inconvenient. Nanotechnology offers promise as a novel means of drug delivery. A capsule-like nanoporous miniature device (NMD) based on a biodegradable polymer, poly(polycaprolactone) (PCL) was developed for controlling the local delivery of immunological agents to the tumor microenvironment. The device consists of a nanoporous release gate, a fabricated drug reservoir loaded with IFN-α and a protective layer. To improve the biocompatibility of the device, a hydrophilic poly(ethylene glycol) monoacrylate was applied to the outside wall of the device via covalent bonding techniques. Microscopic visualization of the nanoporous gate from in vitro experiments exhibited good pore stability over a two-month period. In vitro experiments demonstrated a constant release rate of IFN-α from the NMD and showed that the release rate could be regulated by the gate area. The released IFN-α was biologically functional. Cytokine-containing supernatants from release experiments phosphorylated signal transducer and activator of transcription (STAT1) in peripheral blood mononuclear cells. Subcutaneous implantation of the NMDs was well tolerated and associated with an anti-tumor effect in a human xenograft model of melanoma. There was no evidence of a significant inflammatory response to the NMD or encapsulation of the NMD by fibrosis. These experiments show that the NMD can be fabricated and employed in vivo as a versatile drug delivery platform.
doi:10.1016/j.jconrel.2011.02.020
PMCID: PMC4076956  PMID: 21362447
Biodegradable nanoporous miniature device (NMD); PCL; Nanoporous membrane; Interferon-alpha release; Malignant melanoma
2.  A Small Molecule Screen in Stem Cell-derived Motor Neurons Identifies a Kinase Inhibitor as a Candidate Therapeutic for ALS 
Cell stem cell  2013;12(6):713-726.
Amyotrophic lateral sclerosis (ALS) is a rapidly progressing neurodegenerative disease, characterized by motor neuron (MN) death, for which there are no truly effective treatments. Here, we describe a new small molecule survival screen carried out using MNs from both wildtype and mutant SOD1 mouse embryonic stem cells. Among the hits we found, kenpaullone had a particularly impressive ability to prolong the healthy survival of both types of MNs that can be attributed to its dual inhibition of GSK3 and HGK kinases. Furthermore, kenpaullone also strongly improved the survival of human MNs derived from ALS patient induced pluripotent stem cells and was more active than either of two compounds, olesoxime and dexpramipexole, that recently failed in ALS clinical trials. Our studies demonstrate the value of a stem cell approach to drug discovery and point to a new paradigm for identification and preclinical testing of future ALS therapeutics.
doi:10.1016/j.stem.2013.04.003
PMCID: PMC3707511  PMID: 23602540
3.  In vivo Virus-based Macrofluorogenic Probes Target Azide-labeled Surface Glycans in MCF-7 Breast Cancer Cells 
Molecular pharmaceutics  2012;10(1):43-50.
Chemical addressability of viral particles has played a pivotal role in adapting these biogenic macromolecules for various applications ranging from medicine to inorganic catalysis. The consistent multimeric assemblies dictated by its genetic code, facile large scale production, lack of observable toxicity in humans, Cowpea mosaic virus possesses multiple features that are advantageous for the next generation of virus-based nanotechnology. Herein, the chemistry of the viral particles is extended with the use of Cu-free strain-promoted azide-alkyne cycloaddition reaction, or SPAAC reaction. The elimination of Cu, its co-catalyst and reducing agent simplifies the reaction scheme to a more straightforward approach, which can be directly applied to living systems. As a proof of concept, the viral particles modified with the aza-dibenzylcyclooctynes functional groups are utilized to trigger and amplify a weak fluorescent signal (azidocoumarin) in live cell cultures to visualize the non-natural sugars. Future adaptations of this platform may be developed to enhance biosensing applications.
doi:10.1021/mp3002528
PMCID: PMC4010301  PMID: 22998503
Bionanoparticles; Cowpea mosaic virus; strain-promoted alkyne-azide cycloaddition (SPAAC) reaction; click chemistry; fluorogenic dye; bioconjugation
4.  Targeted Delivery of microRNA-29b by Transferrin Conjugated Anionic Lipopolyplex Nanoparticles: A Novel Therapeutic Strategy in Acute Myeloid Leukemia 
Purpose
miR-29b directly or indirectly targets genes involved in acute myeloid leukemia (AML) i.e., DNMTs, CDK6, SP1, KIT and FLT3. Higher miR-29b pretreatment expression is associated with improved response to decitabine and better outcome in AML. Thus designing a strategy to increase miR-29b levels in AML blasts may be of therapeutic value. However, free synthetic miRs are easily degraded in bio-fluids and have limited cellular uptake. To overcome these limitations, we developed a novel transferrin-conjugated nanoparticle delivery system for synthetic miR-29b (Tf-NP-miR-29b).
Experiment Design
Delivery efficiency was investigated by flow-cytometry, confocal microscopy and quantitative-PCR. The expression of miR-29b targets was measured by immunoblotting. The anti-leukemic activity of Tf-NP-miR-29b was evaluated by measuring cell proliferation and colony formation ability and in a leukemia mouse model.
Results
Tf-NP-miR-29b treatment resulted in >200-fold increase of mature miR-29b compared to free miR-29b and was about twice as efficient as treatment with non-Tf-conjugated NP-miR-29b. Tf-NP-miR-29b treatment significantly downregulated DNMTs, CDK6, SP1, KIT and FLT3 and decreased AML cell growth by 30–50% and impaired colony formation by approximately 50%. Mice engrafted with AML cells and then treated with Tf-NP-miR-29b had significantly longer survival compared to Tf-NP-scramble (P=0.015) or free miR-29b (P=0.003). Furthermore, priming AML cell with Tf-NP-miR-29b before decitabine resulted in strong cell viability decrease in vitro and showed improved anti-leukemic activity compared with decitabine alone (P=0.001) in vivo.
Conclusion
Tf-NP effectively delivered functional miR-29b, resulting in target downregulation and anti-leukemic activity, and warrants further investigation as a novel therapeutic approach in AML.
doi:10.1158/1078-0432.CCR-12-3191
PMCID: PMC3644023  PMID: 23493348
lipopolyplex nanoparticles; miR-29b; Acute Myeloid Leukemia
5.  Comparative cellular pharmacokinetics and pharmacodynamics of siRNA delivery by SPANosomes and by cationic liposomes 
Mechanistic understanding of intracellular trafficking is important for the development of small interfering RNA (siRNA) delivery vehicles. Here, we describe a novel methodology to quantitatively analyze nanocarrier-mediated disposition of siRNA. Cellular uptake and cytoplasmic release of siRNA over time were quantified by measuring the fluorescence intensities of fluorescently-labeled siRNAs and molecular beacons using flow cytometry. This method was used to investigate the cellular pharmacokinetics (PK) of siRNA delivery by SPANosomes (SP) and by cationic liposomes (CL). The results showed that the superior pharmacodynamic (PD) response of SP was because it enhanced transport of siRNA into the cytoplasm compared to the CL. The divergent cellular pharmacokinetic profiles of the two formulations were associated with different cellular entry pathways. These findings can facilitate the rational design of more efficient siRNA delivery vehicles in the future.
doi:10.1016/j.nano.2012.10.002
PMCID: PMC3633702  PMID: 23117046
RNA interference; siRNA; Nanoparticle; Cellular pharmacokinetics; Intracellular trafficking
6.  Enlarged follicles and temporomandibular joint abnormalities in mucolipidosis Type III 
Dentomaxillofacial Radiology  2013;42(4):22822014.
Mucolipidosis Type III, or pseudo-Hurler polydystrophy, is a rare genetic abnormality, the result of a mutation to one of two genes that encode the hexameric protein N-acetylglucosaminyl-1-phosphotransferase (Glc-NAc-PT). The abnormality results in the accumulation of unprocessed macromolecules in cell and tissue compartments throughout the body. In this case report, we describe the clinical and radiographic findings of a 15-year-old male with this disorder. He presented with bilateral ectopically developing mandibular molar teeth with enlarged follicles and multiple joint involvement, including the temporomandibular joints. The patient underwent surgical removal of the molar teeth and curettage of the associated follicles. The subsequent histopathological examination of the tissues revealed hyperplastic follicles suggestive of dentigerous cysts. This report presents the plain film and cone beam CT examinations of the patient.
doi:10.1259/dmfr/22822014
PMCID: PMC3667515  PMID: 22241869
mucolipidosis Type III; temporomandibular joint; impacted teeth
7.  Intraosseous mucoepidermoid carcinoma: a review of the diagnostic imaging features of four jaw cases 
Dentomaxillofacial Radiology  2013;42(4):20110162.
The purpose of this case series is to present the common features of intraosseous mucoepidermoid carcinoma (IMC) of the jaws in plain film and CT imaging. Two oral and maxillofacial radiologists reviewed and characterized the common features of four biopsy-proven cases of IMC in the jaws in plain film and CT imaging obtained from the files of the Department of Oral Radiology, Faculty of Dentistry, University of Toronto, Toronto, Canada. The common features are a well-defined sclerotic periphery, the presence of internal amorphous sclerotic bone and numerous small loculations, lack of septae bordering many of the loculations, and expansion and perforation of the outer cortical plate with extension into surrounding soft tissue. Other characteristics include tooth displacement and root resorption. The four cases of IMC reviewed have common imaging characteristics. All cases share some diagnostic imaging features with other multilocular-appearing entities of the jaws. However, the presence of amorphous sclerotic bone and malignant characteristics can be useful in the differential diagnosis.
doi:10.1259/dmfr.20110162
PMCID: PMC3667517  PMID: 23524908
intraosseous mucoepidermoid carcinoma; central mucoepidermoid carcinoma; diagnostic imaging features; radiographic features
8.  Effects of dna-dependent protein kinase inhibition by NU7026 on dna repair and cell survival in irradiated gastric cancer cell line N87 
Current Oncology  2014;21(2):91-96.
Repair of radiation-induced dna double-strand breaks is a key mechanism in cancer cell radio-resistance. The synthesized compound NU7026 specifically inhibits dna-dependent protein kinase (dna-pk) within the non-homologous end-joining repair mechanism. Earlier studies demonstrated increased radiosensitivity in dna-pk deficient cells compared with wild-type cells. In chronic leukemia cells, NU7026 appears to enhance the cytotoxic effect of chlorambucil. The radio-modifying effects of NU7026 on cell survival, cell cycle, apoptosis, and dna double-strand break repair have yet to be studied in gastric cancer cells.
Methods
The gastric cancer cell line N87 was treated with 0 Gy or 4 Gy in the presence of NU7026 at a dose range of 0–20 μmol/L. Clonogenic assays were used to assess cell survival after treatment. Cell-cycle distribution was analyzed using propidium iodide with fluorescence-activated cell sorting. Apoptosis was detected using annexin-V and propidium iodide with fluorescence-activated cell sorting. The γH2AX assay was used to measure dna double-strand breaks.
Results
Statistically significant increases in G2/M arrest were observed in N87 cells treated with radiation and NU7026 compared with those treated with radiation alone (p = 0.0004). Combined treatment also led to an increase in apoptosis (p = 0.01). At 24 hours, the γH2AX analysis revealed more dna double-strand breaks in N87 cells treated with radiation and NU7026 than in those treated with radiation alone (p = 0.04). Clonogenic assays demonstrated declining cell survival as both the radiation and the NU7026 dose increased. The dose enhancement factor at 0.1 survival fraction was 1.28 when N87 cells were treated with 4 Gy radiation and 5 μmol/L NU7026.
Conclusions
In gastric cancer cells, NU7026 appears to enhance the cytotoxic effect of irradiation as assessed by clonogenic assays. This increased cytotoxicity might be the result of an increase in dna double-strand breaks resulting in G2/M cell arrest and possibly higher levels of apoptosis.
doi:10.3747/co.21.1509
PMCID: PMC3997448  PMID: 24764698
Gastric cancer; dna pk inhibitor; NU7026; radiation therapy; radiosensitization
9.  Incidence of central nervous system metastases in patients with HER2-positive metastatic breast cancer treated with pertuzumab, trastuzumab, and docetaxel: results from the randomized phase III study CLEOPATRA 
Annals of Oncology  2014;25(6):1116-1121.
This manuscript presents exploratory analyses of the incidence and time to development of CNS metastases in patients with first-line HER2-positive metastatic breast cancer in the CLEOPATRA study of pertuzumab, trastuzumab, and docetaxel. The results showed that pertuzumab, trastuzumab, and docetaxel delayed the onset of CNS disease compared with placebo, trastuzumab, and docetaxel.
Background
Results from the phase III trial CLEOPATRA in human epidermal growth factor receptor 2-positive first-line metastatic breast cancer demonstrated significant improvements in progression-free and overall survival with pertuzumab, trastuzumab, and docetaxel over placebo, trastuzumab, and docetaxel. We carried out exploratory analyses of the incidence and time to development of central nervous system (CNS) metastases in patients from CLEOPATRA.
Patients and methods
Patients received pertuzumab/placebo: 840 mg in cycle 1, then 420 mg; trastuzumab: 8 mg/kg in cycle 1, then 6 mg/kg; docetaxel: initiated at 75 mg/m2. Study drugs were administered i.v. every 3 weeks. The log-rank test was used for between-arm comparisons of time to CNS metastases as first site of disease progression and overall survival in patients with CNS metastases as first site of disease progression. The Kaplan–Meier approach was used to estimate median time to CNS metastases as first site of disease progression and median overall survival.
Results
The incidence of CNS metastases as first site of disease progression was similar between arms; placebo arm: 51 of 406 (12.6%), pertuzumab arm: 55 of 402 (13.7%). Median time to development of CNS metastases as first site of disease progression was 11.9 months in the placebo arm and 15.0 months in the pertuzumab arm; hazard ratio (HR) = 0.58, 95% confidence interval (CI) 0.39–0.85, P = 0.0049. Overall survival in patients who developed CNS metastases as first site of disease progression showed a trend in favor of pertuzumab, trastuzumab, and docetaxel; HR = 0.66, 95% CI 0.39–1.11. Median overall survival was 26.3 versus 34.4 months in the placebo and pertuzumab arms, respectively. Treatment comparison of the survival curves was not statistically significant for the log-rank test (P = 0.1139), but significant for the Wilcoxon test (P = 0.0449).
Conclusions
While the incidence of CNS metastases was similar between arms, our results suggest that pertuzumab, trastuzumab, and docetaxel delays the onset of CNS disease compared with placebo, trastuzumab, and docetaxel.
ClinicalTrials.gov
NCT00567190.
doi:10.1093/annonc/mdu133
PMCID: PMC4037862  PMID: 24685829
central nervous system; HER2; metastatic breast cancer; pertuzumab; trastuzumab
10.  A TALEN genome editing system to generate human stem cell-based disease models 
Cell stem cell  2012;12(2):238-251.
SUMMARY
Transcription activator-like effector nucleases (TALENs) are a new class of engineered nucleases that are easier to design to cleave at desired sites in a genome than previous types of nucleases. We report the use of TALENs to rapidly and efficiently generate mutant alleles of 15 genes in cultured somatic cells or human pluripotent stem cells, the latter of which we differentiated both the targeted lines and isogenic control lines into various metabolic cell types. We demonstrate cell-autonomous phenotypes directly linked to disease—dyslipidemia, insulin resistance, hypoglycemia, lipodystrophy, motor neuron death, and hepatitis C infection. We find little evidence of TALEN off-target effects, but each clonal line nevertheless harbors a significant number of unique mutations. Given the speed and ease with which we were able to derive and characterize these cell lines, we anticipate TALEN-mediated genome editing of human cells becoming a mainstay for the investigation of human biology and disease.
doi:10.1016/j.stem.2012.11.011
PMCID: PMC3570604  PMID: 23246482
11.  Selective Identification of Hedgehog Pathway Antagonists By Direct Analysis of Smoothened Ciliary Translocation 
ACS chemical biology  2012;7(6):1040-1048.
Hedgehog (Hh) signaling promotes tumorigenesis. The accumulation of a membrane protein Smoothened (Smo) within the primary cilium (PC) is a key event in Hh signal transduction and many pharmacological inhibitors identified to date target Smo’s actions. Smo ciliary translocation is inhibited by some pathway antagonists while others promote ciliary accumulation; an outcome that can lead to a hypersensitive state on renewal of Hh signaling. To identify novel inhibitory compounds acting on the critical mechanistic transition of Smo accumulation, we established a high content screen to directly analyze Smo ciliary translocation. Screening thousands of compounds from annotated libraries of approved drugs and other agents, we identified several new classes of compounds that block Sonic hedgehog-driven Smo localization within the PC. Selective analysis was conducted on two classes of Smo antagonists. One of these, DY131, appears to inhibit Smo signaling through a common binding site shared by previously reported Smo agonists and antagonists. Antagonism by this class of compound is competed by high doses of Smo-binding agonists such as SAG, and impaired by a mutation that generates a ligand independent, oncogenic form of Smo (SmoM2). In contrast, a second antagonist of Smo accumulation within the PC, SMANT, was less sensitive to SAG-mediated competition, and inhibited SmoM2 at similar concentrations to those that inhibit wild-type Smo. Our observations identify important differences among Hh antagonists and the potential for development of novel therapeutic approaches against mutant forms of Smo that are resistant to current therapeutic strategies.
doi:10.1021/cb300028a
PMCID: PMC3905677  PMID: 22554036
12.  Household Income and Subjective Well-Being after Spinal Cord Injury: A Longitudinal Study 
Background:
Studies regarding subjective well-being (SWB) after spinal cord injury (SCI) are increasing in recent years, but little has been contributed to the relationship between income and SWB.
Objective:
By using longitudinal data, we want to identify (1) the overall trend in SWB over a 10-year period; (2) the association between household income and SWB at baseline; (3) the variation of the trajectory of SWB over 10 years among different household income groups; and (4) the variation of change rates of SWB over 10 years among different household income groups.
Methods:
We conducted a cohort study, including 434 participants who completed 3 measurements in 1998, 2003, and 2008. They were identified from outpatient records of 2 midwestern hospitals and a southeastern specialty hospital.
Results:
People with lower household income experienced more life problems and less life satisfaction at the baseline measurement. During the 10-year period, their health problems and environmental barriers significantly increased compared to persons with higher income. Increasing vocational satisfaction was the only favorable change for the lower income group.
Conclusions:
There were consistent disparities in SWB related to income, and these typically persisted over time. Therefore, with the exception of vocational satisfaction, few changes may be anticipated in SWB that would narrow the gap between high and low income.
doi:10.1310/sci2001-40
PMCID: PMC3919693  PMID: 24574821
income; life problem; life satisfaction; spinal cord injury; subjective well-being
13.  Theoretical Risk and Prevention Model for Secondary Health Conditions and Mortality after SCI: 15 Years of Research 
Background
To successfully prevent secondary health conditions (SHCs) and promote longevity after spinal cord injury (SCI), we must first understand the risk factors precipitating their occurrence and develop strategies to address these risk factors. Conceptual models may aid in identifying the nature of SHCs and guide research, clinical practice, and the development of prevention strategies.
Objective
Our purpose is to review and refine an existing theoretical risk and prevention model (TRPM) as a means of classifying risk and protective factors for SHCs and mortality after SCI and for identifying points of intervention.
Methods
We describe conceptual work within the field of SCI research and SHCs, including a description of the TRPM, a review of research using the TRPM, and conceptual enhancements to the TRPM based on previous research.
Conclusions
The enhanced TRPM directs research to the timing and chronicity of the SHCs and their relationship with overall health and physiologic decline. Future research should identify differences in the nature of SHCs, the extent to which they relate to risk and protective factors, and the degree to which they may be prevented with appropriate research-based strategies.
doi:10.1310/sci1901-15
PMCID: PMC3584350  PMID: 23459002
health; longevity; mortality; risk; spinal cord injury; theoretical models
14.  RGD-conjugated rod-like viral nanoparticles on 2D scaffold improve bone differentiation of mesenchymal stem cells 
Viral nanoparticles have uniform and well-defined nano-structures and can be produced in large quantities. Several plant viral nanoparticles have been tested in biomedical applications due to the lack of mammalian cell infectivity. We are particularly interested in using Tobacco mosaic virus (TMV), which has been demonstrated to enhance bone tissue regeneration, as a tunable nanoscale building block for biomaterials development. Unmodified TMV particles have been shown to accelerate osteogenic differentiation of adult stem cells by synergistically upregulating bone morphogenetic protein 2 (BMP2) and integrin-binding bone sialoprotein (IBSP) expression with dexamethasone. However, their lack of affinity to mammalian cell surface resulted in low initial cell adhesion. In this study, to increase cell binding capacity of TMV based material the chemical functionalization of TMV with arginine-glycine-aspartic acid (RGD) peptide was explored. An azide-derivatized RGD peptide was “clicked” to tyrosine residues on TMV outer surface via an efficient copper(I) catalyzed azide-alkyne cycloaddition (CuAAC) reaction. The ligand spacing is calculated to be 2–4 nm, which could offer a polyvalent ligand clustering effect for enhanced cell receptor signaling, further promoting the proliferation and osteogenic differentiation of bone marrow-derived mesenchymal stem cells (BMSCs).
doi:10.3389/fchem.2014.00031
PMCID: PMC4034042  PMID: 24904922
viral nanoparticles; RGD peptide; click chemistry; osteogenesis; bone mesenchymal stem cells
15.  A cell-autonomous defect in skeletal muscle satellite cells expressing low levels of survival of motor neuron protein 
Developmental biology  2012;368(2):10.1016/j.ydbio.2012.05.037.
Mutations in the Survival of Motor Neuron (SMN) gene underlie the development of spinal muscular atrophy (SMA), which currently represents the leading genetic cause of mortality in infants and toddlers. SMA is characterized by degeneration of spinal cord motor neurons and muscle atrophy. Although SMA is often considered to be a motor neuron disease, accumulating evidence suggests that muscle cells themselves may be affected by low levels of SMN. Here, we examine satellite cells, tissue-resident stem cells that play an essential role in the growth and repair of skeletal muscle, isolated from a severe SMA mouse model (Smn−/−; SMN2+/+). We found similar numbers of satellite cells in the muscles of SMA and wild-type (Smn+/+; SMN2+/+) mice at postnatal day 2 (P2), and, when isolated from skeletal muscle using cell surface marker expression, these cells showed comparable survival and proliferative potential. However, SMA satellite cells differentiate abnormally, revealed by the premature expression of muscle differentiation markers, and, especially, by a reduced efficiency in forming myotubes. These phenotypes suggest a critical role of SMN protein in the intrinsic regulation of muscle differentiation and suggest that abnormal muscle development contributes to the manifestation of SMA symptoms.
doi:10.1016/j.ydbio.2012.05.037
PMCID: PMC3851302  PMID: 22705478
Spinal muscular atrophy; Satellite cells; Muscle
16.  Theoretical Risk and Prevention Model for Secondary Health Conditions and Mortality After SCI: 15 Years of Research 
Background:
To successfully prevent secondary health conditions (SHCs) and promote longevity after spinal cord injury (SCI), we must first understand the risk factors precipitating their occurrence and develop strategies to address these risk factors. Conceptual models may aid in identifying the nature of SHCs and guide research, clinical practice, and the development of prevention strategies.
Objective:
Our purpose is to review and refine an existing theoretical risk and prevention model (TRPM) as a means of classifying risk and protective factors for SHCs and mortality after SCI and for identifying points of intervention.
Methods:
We describe conceptual work within the field of SCI research and SHCs, including a description of the TRPM, a review of research using the TRPM, and conceptual enhancements to the TRPM based on previous research.
Conclusions:
The enhanced TRPM directs research to the timing and chronicity of the SHCs and their relationship with overall health and physiologic decline. Future research should identify differences in the nature of SHCs, the extent to which they relate to risk and protective factors, and the degree to which they may be prevented with appropriate research-based strategies.
doi:10.1310/sci1901-15
PMCID: PMC3584350  PMID: 23459002
health; longevity; mortality; risk; spinal cord injury; theoretical models
17.  Urinary tuberculosis is associated with the development of urothelial carcinoma but not renal cell carcinoma: a nationwide cohort study in Taiwan 
British Journal of Cancer  2013;109(11):2933-2940.
Background:
Obstructive uropathy and chronic urinary tract infection increase the risk of urinary tract cancer. Urinary tuberculosis (UTB) can cause chronic urinary tract inflammation, lead to obstructive uropathy, and potentially contribute to the development of urinary tract cancer. However, the association between UTB and urinary tract cancer has not been studied.
Methods:
This study enrolled 135 142 tuberculosis (TB) cases (male, 69%) from a nationwide health insurance research database in Taiwan and investigated the risk factors for urinary tract cancer, with emphasis on a history of UTB. The incidence of urinary tract cancer in the general population without TB was also calculated for comparison.
Results:
The TB patients had a mean age of 57.5±19.5 years. Of the 1287 UTB and 133 855 non-UTB patients, 15 (1.2%) and 396 (0.3%) developed urothelial carcinoma, respectively (P<0.001); and 2 (0.2%) and 96 (0.1%) developed renal cell carcinoma, respectively (P=0.240). Cox regression analysis revealed that age, male sex, end-stage renal disease, obstructive uropathy, arsenic intoxication, organ transplantation, and UTB (hazard ratio: 3.38 (2.01–5.69)) were independent risk factors for urothelial carcinoma. The hazard ratio of UTB was higher among female patients (5.26 (2.12–13.06)) than that among male patients (2.96 (1.57–5.60)).
Conclusion:
Urinary tuberculosis had a strong association with urothelial carcinoma, but not with renal cell carcinoma. In TB endemic areas, the urinary tract of TB patients should be scrutinised. It is also imperative that these patients be followed-up carefully in the post-treatment period, and urinalysis, ultrasonography or endoscopy should be an integral part of the follow-up.
doi:10.1038/bjc.2013.538
PMCID: PMC3844900  PMID: 24129236
cohort study; obstructive uropathy; Taiwan; tuberculosis; urinary tract cancer; National Health Insurance Research Database
18.  Endogenous knockdown of survivin improves chemotherapeutic response in ALL models 
Leukemia  2011;26(2):10.1038/leu.2011.199.
Although the cure rate of newly diagnosed acute lymphoblastic leukemia (ALL) has improved over the past four decades, the outcome for patients who relapse remains poor. New therapies are needed for these patients. Our previous global gene expression analysis in a series of paired diagnosis-relapse pediatric patient samples revealed that the antiapoptotic gene survivin was consistently upregulated upon disease relapse. In this study, we demonstrate a link between survivin expression and drug resistance and test the efficacy of a novel antisense agent in promoting apoptosis when combined with chemotherapy. Gene-silencing experiments targeting survivin mRNA using either short-hairpin RNA (shRNA) or a locked antisense oligonucleotide (LNA-ON) specifically reduced gene expression and induced apoptosis in leukemia cell lines. When used in combination with chemotherapy, the survivin shRNA and LNA-ON potentiated the chemotherapeutic antileukemia effect. Moreover, in a mouse primary xenograft model of relapse ALL, the survivin LNA-ON decreased survivin expression in a subset of animals, and produced a statistically significant decrease in tumor progression. Taken together, these findings suggest that targeting endogenous levels of survivin mRNA by LNA-ON methods may augment the response to standard chemotherapy by sensitizing otherwise resistant tumor cells to chemotherapy.
doi:10.1038/leu.2011.199
PMCID: PMC3833621  PMID: 21844871
survivin; pediatric; acute lymphoblastic leukemia; EZN-3042
19.  The prolonged survival of fibroblasts with forced lipid catabolism in visceral fat following encapsulation in alginate-poly-L-lysine 
Biomaterials  2012;33(22):10.1016/j.biomaterials.2012.04.035.
Although alginate-poly-L-lysine (APL) encapsulation of cells producing bioactive peptides has been widely tested, it is unknown whether APL supports lasting catabolic functions of encapsulated cells in adipose tissue, which are required for obesity reduction. We tested functions of APL-encapsulated fibroblasts isolated from wild-type (WT) and aldehyde dehydrogenase 1a1 knockout mice (KO), which resist obesity on a high-fat (HF) diet, have a higher metabolic rate, and express increased levels of thermogenic uncoupling protein-1 (Ucp1) in their deleterious visceral fat depots compared to WT mice. To enable in vivo detection and quantification, fibroblasts were stably transfected with green-fluorescent protein. WT- or KO-containing microcapsules were injected into two visceral depots of WT mice fed an HF diet. Eighty days after transplantation, microcapsules were located in vivo using magnetic resonance imaging. KO microcapsules prevented weight gain in obese WT mice compared to a mock- and WT capsule-injected groups on an HF diet. The weight loss in KO-treated mice corresponded to lipid reduction and induction of thermogenesis in the injected visceral fat. The non-treated subcutaneous fat was not altered. Our data suggest that the APL polymer supports long-term catabolic functions of genetically-modified fibroblasts, which can be potentially used for depot-specific obesity treatment.
doi:10.1016/j.biomaterials.2012.04.035
PMCID: PMC3815596  PMID: 22575837
Vitamin A; Aldehyde dehydrogenase; Abdominal obesity; Insulin resistance; Magnetic resonance imaging; Laser capture microdissection; Alginate-poly-L-lysine; Uncoupling protein 1; Thermogenesis; Lipolysis; Retinoids
20.  Risk of Fall-Related Injuries among Ambulatory Participants with Spinal Cord Injury 
Background:
With medical and rehabilitation advances, many people are able to regain or maintain ambulation after spinal cord injury (SCI). However, those who are ambulatory may be at increased risk for falls.
Objective:
To assess the relationships between walking devices and behaviors, including alcohol use, prescription medication use, and exercise, with falls among persons with SCI who are ambulatory.
Methods:
A total of 515 adults with chronic SCI who were able to ambulate provided self-report of their use of assistive devices for ambulation, prescription medication use, alcohol use, exercise, and falls resulting in injury (FRI).
Results:
At least 1 FRI was reported by 20.3% of participants in the past year. Ambulatory participants who reported using a wheelchair as their primary mode of mobility were less likely to have an FRI than those who reported walking more than using a wheelchair. Those with perceived poor balance were 2.41 times more likely to have an FRI than those without poor balance. Those who reported less exercise than other persons with a comparable SCI severity were 2.77 times more likely to have an FRI than those reporting the same or more amount of exercise. Pain medication misuse also was associated with higher odds of an FRI.
Conclusions:
Health care providers should be aware of the risk for FRI among those who are ambulatory. They should assess and consider not only ambulatory ability, but also behaviors, including prescription medication use and exercise, when recommending ambulation techniques.
doi:10.1310/sci1904-259
PMCID: PMC3816720  PMID: 24244091
behavior; exercise; fall; pain medication; spinal cord injury
21.  Jun dimerization protein 2 is a critical component of the Nrf2/MafK complex regulating the response to ROS homeostasis 
Cell Death & Disease  2013;4(11):e921-.
Oxidative stress and reactive oxygen species (ROS) are associated with diseases such as cancer, cardiovascular complications, inflammation and neurodegeneration. Cellular defense systems must work constantly to control ROS levels and to prevent their accumulation. We report here that the Jun dimerization protein 2 (JDP2) has a critical role as a cofactor for transcription factors nuclear factor-erythroid 2-related factor 2 (Nrf2) and small Maf protein family K (MafK) in the regulation of the antioxidant-responsive element (ARE) and production of ROS. Chromatin immunoprecipitation–quantitative PCR (qPCR), electrophoresis mobility shift and ARE-driven reporter assays were carried out to examine the role of JDP2 in ROS production. JDP2 bound directly to the ARE core sequence, associated with Nrf2 and MafK (Nrf2–MafK) via basic leucine zipper domains, and increased DNA-binding activity of the Nrf2–MafK complex to the ARE and the transcription of ARE-dependent genes. In mouse embryonic fibroblasts from Jdp2-knockout (Jdp2 KO) mice, the coordinate transcriptional activation of several ARE-containing genes and the ability of Nrf2 to activate expression of target genes were impaired. Moreover, intracellular accumulation of ROS and increased thickness of the epidermis were detected in Jdp2 KO mice in response to oxidative stress-inducing reagents. These data suggest that JDP2 is required to protect against intracellular oxidation, ROS activation and DNA oxidation. qPCR demonstrated that several Nrf2 target genes such as heme oxygenase-1, glutamate–cysteine ligase catalytic and modifier subunits, the notch receptor ligand jagged 1 and NAD(P)H dehydrogenase quinone 1 are also dependent on JDP2 for full expression. Taken together, these results suggest that JDP2 is an integral component of the Nrf2–MafK complex and that it modulates antioxidant and detoxification programs by acting via the ARE.
doi:10.1038/cddis.2013.448
PMCID: PMC3847324  PMID: 24232097
JDP2; Nrf2–MafK; ROS regulation; antioxidant enzymes; antioxidation
22.  Liposomes Containing (−)-Gossypol-Enriched Cottonseed Oil Suppress Bcl-2 and Bcl-xL Expression in Breast Cancer Cells 
Pharmaceutical research  2011;28(12):10.1007/s11095-011-0498-2.
Purpose
We have demonstrated that (−)-gossypol-enriched cottonseed oil [(−)-GPCSO] can down-regulate Bcl-2 expression in MCF-7 and primary cultured human breast cancer epithelial cells (PCHBCECs). However, this agent has not been evaluated in vivo due to its limited solubility. We aimed to develop liposomes containing (−)-GPCSO to suppress Bcl-2/Bcl-xL expression.
Methods
(−)-GPCSO liposomes were prepared and evaluated for effects on breast cancer cell viability, MDA-MB-231 xenograft tumor growth, cellular Bcl-2 and Bcl-xL mRNA levels, and chemosensitivity to paclitaxel.
Results
(−)-GPCSO liposomes prepared had excellent stability. Cytotoxicity of (−)-GPCSO liposomes was significantly reduced compared to (−)-GPCSO in culture medium. Bcl-2 and Bcl-xL mRNA expression was down-regulated by (−)-GPCSO in culture medium or (−)-GPCSO liposomes in MDA-MB-231 cells. In PCHBCECs, Bcl-2 and Bcl-xL expression were down-regulated by (−)-GPCSO liposomes. (−)-GPCSO in culture medium induced only a mild reduction in Bcl-xL. In the MDA-MB-231 xenograft tumor model, (−)-GPCSO liposomes exhibited tumor-suppressive activity and significantly reduced intratumoral Bcl-2 and Bcl-xL expression. Cytotoxicity of paclitaxel was increased by pretreatment with (−)-GPCSO liposomes in MDA-MB-231 and PCHBCECs.
Conclusions
Findings suggest that (−)-GPCSO liposomes warrant continued investigation as a chemosensitizer for breast cancers exhibiting Bcl-2-/Bcl-xL-mediated drug resistance.
doi:10.1007/s11095-011-0498-2
PMCID: PMC3809120  PMID: 21710341
(−)-gossypol; Bcl-2; Bcl-xL; chemoresistance; liposomes
23.  Optical magnetic imaging of living cells 
Nature  2013;496(7446):486-489.
Magnetic imaging is a powerful tool for probing biological and physical systems. However, existing techniques either have poor spatial resolution compared to optical microscopy and are hence not generally applicable to imaging of sub-cellular structure (e.g., magnetic resonance imaging [MRI]1), or entail operating conditions that preclude application to living biological samples while providing sub-micron resolution (e.g., scanning superconducting quantum interference device [SQUID] microscopy2, electron holography3, and magnetic resonance force microscopy [MRFM]4). Here we demonstrate magnetic imaging of living cells (magnetotactic bacteria) under ambient laboratory conditions and with sub-cellular spatial resolution (400 nm), using an optically-detected magnetic field imaging array consisting of a nanoscale layer of nitrogen-vacancy (NV) colour centres implanted at the surface of a diamond chip. With the bacteria placed on the diamond surface, we optically probe the NV quantum spin states and rapidly reconstruct images of the vector components of the magnetic field created by chains of magnetic nanoparticles (magnetosomes) produced in the bacteria, and spatially correlate these magnetic field maps with optical images acquired in the same apparatus. Wide-field sCMOS acquisition allows parallel optical and magnetic imaging of multiple cells in a population with sub-micron resolution and >100 micron field-of-view. Scanning electron microscope (SEM) images of the bacteria confirm that the correlated optical and magnetic images can be used to locate and characterize the magnetosomes in each bacterium. The results provide a new capability for imaging bio-magnetic structures in living cells under ambient conditions with high spatial resolution, and will enable the mapping of a wide range of magnetic signals within cells and cellular networks5, 6.
doi:10.1038/nature12072
PMCID: PMC3641584  PMID: 23619694
24.  Cationic lipid-coated magnetic nanoparticles associated with transferrin for gene delivery 
International journal of pharmaceutics  2008;358(0):10.1016/j.ijpharm.2008.02.020.
Cationic lipid-coated magnetic nanoparticles (MPs) associated with transferrin were evaluated as gene transfer vectors in the presence of a static magnetic field. MPs were prepared by chemical precipitation and were surface-coated with cationic lipids, composed of DDAB/soy PC (60:40 mole/mole). These cationic MPs were then combined with polyethylenimine (PEI) condensed plasmid DNA, followed by transferrin. The resulting magnetic electrostatic complexes retained relatively compact particle size and showed complete DNA condensation. Their transfection activity in the presence of a static magnetic field was evaluated by luciferase and green fluorescent protein (GFP) reporter genes. The magnetic complexes exhibited up to 300-fold higher transfection activity compared to commonly used cationic liposomes or cationic polymer complexes, based on luciferase assay. The enhancement in transfection activity was maximized when the cells were exposed to the vectors for a relatively short period of time (15 min), or were treated in media containing 10% serum. Incorporation of transferrin further improved transfection efficiency of the cationic MPs. However, when cells were incubated for 4 h in serum-free media, magnetic and non-magnetic vectors showed similar transfection efficiencies. In conclusion, transferrin-associated cationic MPs are excellent gene transfer vectors that can mediate very rapid and efficient gene transfer in vitro in the presence of a magnetic field.
doi:10.1016/j.ijpharm.2008.02.020
PMCID: PMC3807797  PMID: 18384982
Gene delivery; Magnetic nanoparticles; Transferrin; Cationic lipid; Magnetofection
25.  Transferrin-conjugated lipid-coated PLGA nanoparticles for targeted delivery of aromatase inhibitor 7α-APTADD to breast cancer cells 
International journal of pharmaceutics  2010;390(2):10.1016/j.ijpharm.2010.02.008.
Transferrin (Tf)-conjugated lipid-coated poly(d,l-lactide-co-glycolide) (PLGA) nanoparticles carrying the aromatase inhibitor, 7α-(4′-amino)phenylthio-1,4-androstadiene-3,17-dione (7α-APTADD), were synthesized by a solvent injection method. Formulation parameters including PLGA-to-lipid, egg PC-to-TPGS, and drug-to-PLGA ratios and aqueous-to-organic phase ratio at the point of synthesis were optimized to obtain nanoparticles with desired sizes and drug loading efficiency. The optimal formulation had a drug loading efficiency of 36.3±3.4%, mean diameter of 170.3±7.6 nm and zeta potential of −18.9±1.5 mV. The aromatase inhibition activity of the nanoparticles was evaluated in SKBR-3 breast cancer cells. IC50 value of the Tf-nanoparticles was ranging from 0.77 to 1.21 nM, and IC50 value of the nanoparticles was ranging from 1.90 to 3.41 nM (n = 3). The former is significantly lower than the latter (p < 0.05). These results suggested that the aromatase inhibition activity of the Tf-nanoparticles was enhanced relative to that of the non-targeted nanoparticles, which was attributable to Tf receptor (TfR) mediated uptake. In conclusion, Tf-conjugated lipid-coated PLGA nanoparticles are potential vehicles for improving the efficiency and specificity of therapeutic delivery of aromatase inhibitors.
doi:10.1016/j.ijpharm.2010.02.008
PMCID: PMC3807850  PMID: 20156537
Aromatase inhibitor; PLGA nanoparticle; Transferrin receptor; 7α-APTADD; Drug targeting

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