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1.  Pro-metastatic GPCR CD97 is a Direct Target of Tumor Suppressor microRNA-126 
ACS chemical biology  2013;9(2):334-338.
Tumor suppressor microRNA-126 (miR-126) is often down-regulated in cancer cells, and its over-expression is found to inhibit cancer metastasis. To elucidate the mechanism of tumor suppression by miR-126, we analyzed the proteomic response to miR-126 over-expression in the human metastatic breast cancer cell line MDA-MB-231. To acquire quantitative, time-resolved information, we combined two complementary proteomic methods, BONCAT and SILAC. We discovered a new direct target of miR-126: CD97, a pro-metastatic G-protein-coupled receptor (GPCR) that has been reported to promote tumor cell invasion, endothelial cell migration and tumor angiogenesis. This discovery establishes a link between down-regulation of miR-126 and over-expression of CD97 in cancer, and provides new mechanistic insight into the role of miR-126 in inhibiting both cell-autonomous and non-cell-autonomous cancer progression.
PMCID: PMC3944050  PMID: 24274104
2.  Effects of rapamycin against paraquat-induced pulmonary fibrosis in mice*  
Background and aims: Ingestion of paraquat (PQ), a widely used herbicide, can cause severe toxicity in humans, leading to a poor survival rate and prognosis. One of the main causes of death by PQ is PQ-induced pulmonary fibrosis, for which there are no effective therapies. The aim of this study was to evaluate the effects of rapamycin (RAPA) on inhibiting PQ-induced pulmonary fibrosis in mice and to explore its possible mechanisms. Methods: Male C57BL/6J mice were exposed to either saline (control group) or PQ (10 mg/kg body weight, intraperitoneally; test group). The test group was divided into four subgroups: a PQ group (PQ-exposed, non-treated), a PQ+RAPA group (PQ-exposed, treated with RAPA at 1 mg/kg intragastrically), a PQ+MP group (PQ-exposed, treated with methylprednisolone (MP) at 30 mg/kg intraperitoneally), and a PQ+MP+RAPA group (PQ-exposed, treated with MP at 30 mg/kg intraperitoneally and with RAPA at 1 mg/kg intragastrically). The survival rate and body weight of all the mice were recorded every day. Three mice in each group were sacrificed at 14 d and the rest at 28 d after intoxication. Lung tissues were excised and stained with hematoxylin-eosin (H&E) and Masson’s trichrome stain for histopathological analysis. The hydroxyproline (HYP) content in lung tissues was detected using an enzyme-linked immunosorbent assay (ELISA) kit. The expression of transforming growth factor-β1 (TGF-β1) and α-smooth muscle actin (α-SMA) in lung tissues was detected by immunohistochemical staining and Western blotting. Results: A mice model of PQ-induced pulmonary fibrosis was established. Histological examination of lung tissues showed that RAPA treatment moderated the pathological changes of pulmonary fibrosis, including alveolar collapse and interstitial collagen deposition. HYP content in lung tissues increased soon after PQ intoxication but had decreased significantly by the 28th day after RAPA treatment. Immunohistochemical staining and Western blotting showed that RAPA treatment significantly down-regulated the enhanced levels of TGF-β1 and α-SMA in lung tissues caused by PQ exposure. However, RAPA treatment alone could not significantly ameliorate the lower survival rate and weight loss of treated mice. MP treatment enhanced the survival rate, but had no significant effects on attenuating PQ-induced pulmonary fibrosis or reducing the expression of TGF-β1 and α-SMA. Conclusions: This study demonstrates that RAPA treatment effectively suppresses PQ-induced alveolar collapse and collagen deposition in lung tissues through reducing the expression of TGF-β1 and α-SMA. Thus, RAPA has potential value in the treatment of PQ-induced pulmonary fibrosis.
PMCID: PMC4288945  PMID: 25559956
Paraquat; Pulmonary fibrosis; Rapamycin; Transforming growth factor-β1; α-Smooth muscle actin; Methylprednisolone
3.  Effects of chlorin e6-mediated photodynamic therapy on human colon cancer SW480 cells 
Objective: This study is to investigate the antitumor effects and possible mechanisms of chlorin e6-mediated photodynamic therapy (Ce6-PDT) on human colon cancer SW480 cells. Methods: SW480 cells were treated with Ce6, followed by photodynamic irradiation. Subcellular localization of Ce6 in SW480 cells was observed with confocal laser scanning microscopy (LSCM). Reactive oxygen species (ROS) levels were monitored with fluorescence microscopy. Cell proliferation and apoptosis were detected by the MTT assay and flow cytometry, respectively. Scratch test and colony formation assay were employed to analyze the cell migration ability and colony formation ability. Results: LSCM showed that, in SW480 cells, Ce6 was evenly distributed within the ER and lysosomes, with nearly no distribution in the mitochondria and nuclei. When SW480 cells were subjected to Ce6-PDT, the ROS levels would be elevated, in a dose-dependent manner. Moreover, Ce6-PDT treatment could inhibit the cell proliferation and enhance the apoptotic process, in SW480 cells. However, Ce6 treatment alone without photodynamic irradiation could not induce any significant differences in the cell proliferation and apoptosis. In addition, the migration ability and colony formation ability of SW480 cells were decreased by Ce6-PDT treatment at appropriate dosages. Conclusion: Ce6-PDT treatment could enhance ROS production and apoptosis, inhibit cell proliferation, decrease migration ability and colony formation ability, in SW480 cells, in a dose-dependent manner. These findings might provide experimental evidence for the application of Ce6-PDT in clinical treatment of colorectal cancer.
PMCID: PMC4307430  PMID: 25663983
Colorectal cancer; chlorin e6; photodynamic therapy; SW480 cells
4.  Cellulolytic potential under environmental changes in microbial communities from grassland litter 
In many ecosystems, global changes are likely to profoundly affect microorganisms. In Southern California, changes in precipitation and nitrogen deposition may influence the composition and functional potential of microbial communities and their resulting ability to degrade plant material. To test whether such environmental changes impact the distribution of functional groups involved in leaf litter degradation, we determined how the genomic diversity of microbial communities in a semi-arid grassland ecosystem changed under reduced precipitation or increased N deposition. We monitored communities seasonally over a period of 2 years to place environmental change responses into the context of natural variation. Fungal and bacterial communities displayed strong seasonal patterns, Fungi being mostly detected during the dry season whereas Bacteria were common during wet periods. Most putative cellulose degraders were associated with 33 bacterial genera and predicted to constitute 18% of the microbial community. Precipitation reduction reduced bacterial abundance and cellulolytic potential whereas nitrogen addition did not affect the cellulolytic potential of the microbial community. Finally, we detected a strong correlation between the frequencies of genera of putative cellulose degraders and cellulase genes. Thus, microbial taxonomic composition was predictive of cellulolytic potential. This work provides a framework for how environmental changes affect microorganisms responsible for plant litter deconstruction.
PMCID: PMC4243572  PMID: 25505459
cellulase; metagenomics; leaf litter; global change; microbial community composition
5.  IL-6 Secreted from Senescent Mesenchymal Stem Cells Promotes Proliferation and Migration of Breast Cancer Cells 
PLoS ONE  2014;9(11):e113572.
Human mesenchymal stem cells (hMSCs) are currently investigated for a variety of therapeutic applications. However, MSCs isolated from primary tissue cannot meet clinical grade needs and should be expanded in vitro for several passages. Although hMSCs show low possibility for undergoing oncogenic transformation, they do, similar to other somatic cells, undergo cellular senescence and their therapeutic potential is diminished when cultured in vitro. However, the role of senescent MSCs in tumor progression remains largely elusive. In the current study, by establishing senescent human umbilical cord mesenchymal stem cells (s-UCMSCs) through the replicative senescence model and genotoxic stress induced premature senescence model, we show that s-UCMSCs significantly stimulate proliferation and migration of breast cancer cells in vitro and tumor progression in a co-transplant xenograft mouse model compared with ‘young’ counterparts (defined as MSCs at passage 5, in contrast to senescent MSCs at passage 45). In addition, we identified IL-6, a known pleiotropic cytokine, as a principal mediator for the tumor-promoting activity of s-UCMSCs by induction of STAT3 phosphorylation. Depletion of IL-6 from s-UCMSCs conditioned medium partially abrogated the stimulatory effect of s-UCMSCs on the proliferation and migration of breast tumor cells.
PMCID: PMC4242635  PMID: 25419563
6.  Integrating Tobacco Cessation Into Mental Health Care for Posttraumatic Stress Disorder 
JAMA  2010;304(22):2485-2493.
Most smokers with mental illness do not receive tobacco cessation treatment.
To determine whether integrating smoking cessation treatment into mental health care for veterans with posttraumatic stress disorder (PTSD) improves long-term smoking abstinence rates.
Design, Setting, and Patients
A randomized controlled trial of 943 smokers with military-related PTSD who were recruited from outpatient PTSD clinics at 10 Veterans Affairs medical centers and followed up for 18 to 48 months between November 2004 and July 2009.
Smoking cessation treatment integrated within mental health care for PTSD delivered by mental health clinicians (integrated care 7 [IC]) vs referral to Veterans Affairs smoking cessation clinics (SCC). Patients received smoking cessation treatment within 3 months of study enrollment.
Main Outcome Measures
Smoking outcomes included 12-month bioverified prolonged abstinence (primary outcome) and 7- and 30-day point prevalence abstinence assessed at 3-month intervals. Amount of smoking cessation medications and counseling sessions delivered were tested as mediators of outcome. Posttraumatic stress disorder and depression were repeatedly assessed using the PTSD Checklist and Patient Health Questionnaire 9, respectively, to determine if IC participation or quitting smoking worsened psychiatric status.
Integrated care was better than SCC on prolonged abstinence (8.9% vs 4.5%; adjusted odds ratio, 2.26; 95% confidence interval [CI], 1.30-3.91; P=.004). Differences between IC vs SCC were largest at 6 months for 7-day point prevalence abstinence (78/472 [16.5%] vs 34/471 [7.2%], P <.001) and remained significant at 18 months (86/472 [18.2%] vs 51/471 [10.8%], P <.001). Number of counseling sessions received and days of cessation medication used explained 39.1% of the treatment effect. Between baseline and 18 months, psychiatric status did not differ between treatment conditions. Posttraumatic stress disorder symptoms for quitters and nonquitters improved. Nonquitters worsened slightly on the Patient Health Questionnaire 9 relative to quitters (differences ranged between 0.4 and 2.1, P=.03), whose scores did not change overtime.
Among smokers with military-related PTSD, integrating smoking cessation treatment into mental health care compared with referral to specialized cessation treatment resulted in greater prolonged abstinence.
Trial Registration Identifier: NCT00118534
PMCID: PMC4218733  PMID: 21139110
7.  Financial Distress, Use of Cost-Coping Strategies, and Adherence to Prescription Medication Among Patients With Cancer 
Journal of Oncology Practice  2013;9(6 Suppl):60s-63s.
The authors found that cost-related medication nonadherence was prevalent among patients with cancer who sought financial assistance.
The relationship between prescription medication adherence and financial burden is understudied, particularly in patients seeking financial assistance.
We conducted a cross-sectional survey to examine the association between patient-reported prescription medication nonadherence and financial distress. Eligible patients were adults receiving treatment for solid malignancies enrolled between June 2010 and May 2011 from the HealthWell Foundation, a national copay assistance program. Nonadherence was defined as taking less medication than prescribed because of cost, not filling or partially filling a prescription because of cost, or taking medications prescribed for others. Logistic regression assessed associations between medication nonadherence and patient-reported, subjective financial distress.
Among 164 participants, 45% reported cost-related medication nonadherence. Four percent took medications prescribed for another person, 22% took less medication than prescribed, 25% filled a partial prescription, and 27% did not fill a prescription, all as a result of cost. Nonadherent participants were more likely than adherent participants to reduce spending on basics like food and clothing to pay for medication (P = .01), and borrow and/or use credit to pay for medications (P < .01). In adjusted analyses, financial distress did not change odds of nonadherence (odds ratio [OR] = 1.60; 95% CI, 0.71 to 3.60). Having a prescription drug plan (OR = 0.27; 95% CI, 0.09 to 0.83) and older age (OR = 0.48; 95% CI, 0.27 to 0.85) decreased odds of nonadherence. Being unemployed increased odds of nonadherence (OR = 6.28; 95% CI, 1.60 to 24.64).
Cost-related medication nonadherence was prevalent among cancer patients who sought financial assistance. Further investigation is needed to understand predictors of prescription medication adherence, a key component of quality care.
PMCID: PMC3825170
8.  Features of Occult Invasion in Biopsy-Proven DCIS at Breast MRI 
The breast journal  2013;19(6):650-658.
To determine if MRI BI-RADS criteria or radiologist perception correlate with presence of invasive cancer after initial core biopsy of ductal carcinoma in situ (DCIS).
Materials and Methods
Retrospective search spanning 2000-2007 identified all core-biopsy diagnoses of pure DCIS that coincided with preoperative MRI. Two radiologists fellowship-trained in breast imaging categorized lesions according to ACR MRI-BIRADS lexicon and estimated likelihood of occult invasion. Semi-quantitative signal enhancement ratio (SER) kinetic analysis was also performed. Results were compared to histopathology.
51 consecutive patients with primary core biopsy-proven DCIS and concurrent MRI were identified. Of these, 13 patients (25%) had invasion at excision. Invasion correlated significantly with presence of a mass for both readers (p=0.012, 0.001), rapid initial enhancement for Reader 1 (p=0.001), and washout kinetics for Reader 2 (p=0.012). Significant correlation between washout and invasion was confirmed by SER (p=0.006) when threshold percent enhancement was sufficiently high (130%), corresponding to rapidly enhancing portions of the lesion. Radiologist perception of occult invasion was strongly correlated to true presence of invasion.
These results provide evidence that certain BI-RADS MRI criteria, as well as radiologist perception, correlate with occult invasion after an initial core biopsy of DCIS.
PMCID: PMC4036640  PMID: 24165314
breast; carcinoma; ductal carcinoma in situ; invasive ductal carcinoma; invasive lobular carcinoma
9.  Effect of antioxidant treatment on spinal GABA neurons in a neuropathic pain model in the mouse 
Pain  2013;154(11):10.1016/j.pain.2013.07.024.
One feature of neuropathic pain is a reduced spinal GABAergic inhibitory function. However, the mechanisms behind this attenuation remain to be elucidated. This study investigated the involvement of reactive oxygen species in the spinal GABA neuron loss and reduced GABA neuron excitability in spinal nerve ligation (SNL) model of neuropathic pain in mice. The importance of spinal GABAergic inhibition in neuropathic pain was tested by examining the effects of intrathecally administered GABA receptor agonists and antagonists in SNL and naïve mice, respectively. The effects of SNL and antioxidant treatment on GABA neuron loss and functional changes were examined in transgenic GAD67-EGFP mice. GABA receptor agonists transiently reversed mechanical hypersensitivity of the hind paw in SNL mice. On the other hand, GABA receptor antagonists made naïve mice mechanically hypersensitive. Stereological analysis showed that the numbers of enhanced green fluorescent protein positive (EGFP+) GABA neurons were significantly decreased in the lateral superficial laminae (I-II) on the ipsilateral L5 spinal cord after SNL. Repeated antioxidant treatments significantly reduced the pain behaviors and prevented the reduction in EGFP+ GABA neurons. The response rate of the tonic firing GABA neurons recorded from SNL mice increased with antioxidant treatment, whereas no change was seen in those recorded from naïve mice, which suggested that oxidative stress impaired some spinal GABA neuron activity in the neuropathic pain condition. Together the data suggest that neuropathic pain, at least partially, is attributed to oxidative stress which induces both a GABA neuron loss and dysfunction of surviving GABA neurons.
PMCID: PMC3816493  PMID: 23880056
10.  Plk1 Phosphorylation of PTEN Causes a Tumor-Promoting Metabolic State 
Molecular and Cellular Biology  2014;34(19):3642-3661.
One outcome of activation of the phosphatidylinositol 3-kinase (PI3K) pathway is increased aerobic glycolysis, but the upstream signaling events that regulate the PI3K pathway, and thus the Warburg effect, are elusive. Increasing evidence suggests that Plk1, a cell cycle regulator, is also involved in cellular events in addition to mitosis. To test whether Plk1 contributes to activation of the PI3K pathway, and thus aerobic glycolysis, we examined potential targets of Plk1 and identified PTEN as a Plk1 substrate. We hypothesize that Plk1 phosphorylation of PTEN leads to its inactivation, activation of the PI3K pathway, and the Warburg effect. Our data show that overexpression of Plk1 leads to activation of the PI3K pathway and enhanced aerobic glycolysis. In contrast, inhibition of Plk1 causes markedly reduced glucose metabolism in mice. Mechanistically, we show that Plk1 phosphorylation of PTEN and Nedd4-1, an E3 ubiquitin ligase of PTEN, results in PTEN inactivation. Finally, we show that Plk1 phosphorylation of PTEN promotes tumorigenesis in both its phosphatase-dependent and -independent pathways, revealing potentially new drug targets to arrest tumor cell growth.
PMCID: PMC4187734  PMID: 25047839
11.  Rank regression: an alternative regression approach for data with outliers 
Shanghai Archives of Psychiatry  2014;26(5):310-315.
Linear regression models are widely used in mental health and related health services research. However, the classic linear regression analysis assumes that the data are normally distributed, an assumption that is not met by the data obtained in many studies. One method of dealing with this problem is to use semi-parametric models, which do not require that the data be normally distributed. But semi-parametric models are quite sensitive to outlying observations, so the generated estimates are unreliable when study data includes outliers. In this situation, some researchers trim the extreme values prior to conducting the analysis, but the ad-hoc rules used for data trimming are based on subjective criteria so different methods of adjustment can yield different results. Rank regression provides a more objective approach to dealing with non-normal data that includes outliers. This paper uses simulated and real data to illustrate this useful regression approach for dealing with outliers and compares it to the results generated using classical regression models and semi-parametric regression models.
PMCID: PMC4248265
normal distribution; non-normal distribution; linear regression; semi-parametric regression models; rank regression; sexual health
12.  Mechanisms Controlling Arsenic Uptake in Rice Grown in Mining Impacted Regions in South China 
PLoS ONE  2014;9(9):e108300.
Foods produced on soils impacted by Pb-Zn mining activities are a potential health risk due to plant uptake of the arsenic (As) associated with such mining. A field survey was undertaken in two Pb-Zn mining-impacted paddy fields in Guangdong Province, China to assess As accumulation and translocation, as well as other factors influencing As in twelve commonly grown rice cultivars. The results showed that grain As concentrations in all the surveyed rice failed national food standards, irrespective of As speciation. Among the 12 rice cultivars, “SY-89” and “DY-162” had the least As in rice grain. No significant difference for As concentration in grain was observed between the rice grown in the two areas that differed significantly for soil As levels, suggesting that the amount of As contamination in the soil is not necessarily the overriding factor controlling the As content in the rice grain. The iron and manganese plaque on the root surface curtailed As accumulation in rice roots. Based on our results, the accumulation of As within rice plants was strongly associated with such soil properties such as silicon, phosphorus, organic matter, pH, and clay content. Understanding the factors and mechanisms controlling As uptake is important to develop mitigation measures that can reduce the amount of As accumulated in rice grains produced on contaminated soils.
PMCID: PMC4177218  PMID: 25251438
13.  Phylogeny and Divergence Times of Gymnosperms Inferred from Single-Copy Nuclear Genes 
PLoS ONE  2014;9(9):e107679.
Phylogenetic reconstruction is fundamental to study evolutionary biology and historical biogeography. However, there was not a molecular phylogeny of gymnosperms represented by extensive sampling at the genus level, and most published phylogenies of this group were constructed based on cytoplasmic DNA markers and/or the multi-copy nuclear ribosomal DNA. In this study, we use LFY and NLY, two single-copy nuclear genes that originated from an ancient gene duplication in the ancestor of seed plants, to reconstruct the phylogeny and estimate divergence times of gymnosperms based on a complete sampling of extant genera. The results indicate that the combined LFY and NLY coding sequences can resolve interfamilial relationships of gymnosperms and intergeneric relationships of most families. Moreover, the addition of intron sequences can improve the resolution in Podocarpaceae but not in cycads, although divergence times of the cycad genera are similar to or longer than those of the Podocarpaceae genera. Our study strongly supports cycads as the basal-most lineage of gymnosperms rather than sister to Ginkgoaceae, and a sister relationship between Podocarpaceae and Araucariaceae and between Cephalotaxaceae-Taxaceae and Cupressaceae. In addition, intergeneric relationships of some families that were controversial, and the relationships between Taxaceae and Cephalotaxaceae and between conifers and Gnetales are discussed based on the nuclear gene evidence. The molecular dating analysis suggests that drastic extinctions occurred in the early evolution of gymnosperms, and extant coniferous genera in the Northern Hemisphere are older than those in the Southern Hemisphere on average. This study provides an evolutionary framework for future studies on gymnosperms.
PMCID: PMC4164646  PMID: 25222863
14.  Emmprin and KSHV: new partners in viral cancer pathogenesis 
Cancer letters  2013;337(2):161-166.
Emmprin (CD147; basigin) is a multifunctional glycoprotein expressed at higher levels by cancer cells and stromal cells in the tumor microenvironment. Through direct effects within tumor cells and promotion of tumor-stroma interactions, emmprin participates in induction of tumor cell invasiveness, angiogenesis, metastasis and chemoresistance. Although its contribution to cancer progression has been widely studied, the role of emmprin in viral oncogenesis still remains largely unclear, and only a small body of available literature implicates emmprin-associated mechanisms in viral pathogenesis and tumorigenesis. We summarize these data in this review, focusing on the role of emmprin in pathogenesis associated with the Kaposi sarcoma-associated herpesvirus (KSHV), a common etiology for cancers arising in the setting of immune suppression. We also discuss future directions for mechanistic studies exploring roles for emmprin in viral cancer pathogenesis.
PMCID: PMC3728473  PMID: 23743354
KSHV; Kaposi sarcoma; primary effusion lymphoma; emmprin; CD147
15.  Effects of hypoxic exercise training on microRNA expression and lipid metabolism in obese rat livers*  
To investigate the effects of hypoxic exercise training on microRNA (miRNA) expression and the role of miRNA expression in regulating lipid metabolism, 20 dietary-induced obese SD rats were divided into a normoxic sedentary group (N, n=10) and a hypoxic exercise training group (H, n=10). After four weeks, measurements were taken of body weight, body length, fat mass, serum lipid concentration, miRNAs differentially expressed in rat liver, and gene and protein expression levels of peroxisome proliferator activated receptor α (PPARα), fatty acid synthetase (FAS), and carnitine palmitoyl transferase 1A (CPT1A) in rat liver. Body weight, Lee’s index, fat mass, fat/weight ratio, and serum levels of total cholesterol (TC) and high density lipoprotein cholesterol (HDL-C) were all significantly lower in the H group than in the N group (P<0.01). Six miRNAs expressed significantly differently in the liver (P<0.05). Specifically, expression levels of miR-378b were significantly lower in the H group than in the N group (P<0.05). Compared with the normoxic sedentary group, hypoxic exercise training resulted in a lower ratio of FAS mRNA to CPT1A mRNA (P<0.05), as well as lower CPT1A protein levels (P<0.01), while a higher ratio of FAS to CPT1A protein levels (P<0.01) was observed. In conclusion, hypoxic training may elevate the resistance of high fat diet induced obesity in rats by reducing the expression of miR-378b, and decrease the fatty acid mitochondrial oxidation in obese rat livers by decreasing the protein expression of CPT1A and increasing the protein expression ratio of FAS/CPT1A.
PMCID: PMC4162883  PMID: 25183036
Hypoxic training; Obese rat; Liver; MicroRNA; Lipid metabolism
16.  Surface Plasmon Resonance Temperature Sensor Based on Photonic Crystal Fibers Randomly Filled with Silver Nanowires 
Sensors (Basel, Switzerland)  2014;14(9):16035-16045.
We propose a temperature sensor design based on surface plasmon resonances (SPRs) supported by filling the holes of a six-hole photonic crystal fiber (PCF) with a silver nanowire. A liquid mixture (ethanol and chloroform) with a large thermo-optic coefficient is filled into the PCF holes as sensing medium. The filled silver nanowires can support resonance peaks and the peak will shift when temperature variations induce changes in the refractive indices of the mixture. By measuring the peak shift, the temperature change can be detected. The resonance peak is extremely sensitive to temperature because the refractive index of the filled mixture is close to that of the PCF material. Our numerical results indicate that a temperature sensitivity as high as 4 nm/K can be achieved and that the most sensitive range of the sensor can be tuned by changing the volume ratios of ethanol and chloroform. Moreover, the maximal sensitivity is relatively stable with random filled nanowires, which will be very convenient for the sensor fabrication.
PMCID: PMC4208160  PMID: 25177799
temperature sensor; fiber optic sensor; photonic crystal fiber; surface plasmon resonance; silver nanowire; mixture
17.  Effects of Microbubble Size on Ultrasound-Mediated Gene Transfection in Auditory Cells 
BioMed Research International  2014;2014:840852.
Gene therapy for sensorineural hearing loss has recently been used to insert genes encoding functional proteins to preserve, protect, or even regenerate hair cells in the inner ear. Our previous study demonstrated a microbubble- (MB-)facilitated ultrasound (US) technique for delivering therapeutic medication to the inner ear. The present study investigated whether MB-US techniques help to enhance the efficiency of gene transfection by means of cationic liposomes on HEI-OC1 auditory cells and whether MBs of different sizes affect such efficiency. Our results demonstrated that the size of MBs was proportional to the concentration of albumin or dextrose. At a constant US power density, using 0.66, 1.32, and 2.83 μm albumin-shelled MBs increased the transfection rate as compared to the control by 30.6%, 54.1%, and 84.7%, respectively; likewise, using 1.39, 2.12, and 3.47 μm albumin-dextrose-shelled MBs increased the transfection rates by 15.9%, 34.3%, and 82.7%, respectively. The results indicate that MB-US is an effective technique to facilitate gene transfer on auditory cells in vitro. Such size-dependent MB oscillation behavior in the presence of US plays a role in enhancing gene transfer, and by manipulating the concentration of albumin or dextrose, MBs of different sizes can be produced.
PMCID: PMC4164849  PMID: 25254216
18.  Polymeric Micelles and Alternative Nanonized Delivery Vehicles for Poorly Soluble Drugs 
Poorly soluble drugs often encounter low bioavailability and erratic absorption patterns in the clinical setting. Due to the rising number of compounds having solubility issues, finding ways to enhance the solubility of drugs is one of the major challenges in the pharmaceutical industry today. Polymeric micelles, which form upon self-assembly of amphiphilic macromolecules, can act as solubilizing agents for delivery of poorly soluble drugs. This manuscript examines the fundamentals of polymeric micelles through reviews of representative literature and demonstrates possible applications through recent examples of clinical trial developments. In particular, the potential of polymeric micelles for delivery of poorly water-soluble drugs, especially in the areas of oral delivery and in cancer therapy, is discussed. Key considerations in utilizing polymeric micelles’ advantages and overcoming potential disadvantages have been highlighted. Lastly, other possible strategies related to particle size reduction for enhancing solubilization of poorly water-soluble drugs are introduced.
PMCID: PMC3760723  PMID: 22944304
Polymeric micelle; oral delivery; anticancer; drug solubilisation; clinical trial; micelle stability; nanocrystal; nanoemulsion
19.  Hepatitis B surface antigen levels during natural history of chronic hepatitis B: A Chinese perspective study 
AIM: To determine the baseline hepatitis B surface antigen (HBsAg) levels during the different phases of chronic hepatitis B (CHB) patients in China.
METHODS: Six hundred and twenty-three hepatitis B virus or un-infected patients not receiving antiviral therapy were analyzed in a cross-sectional study. The CHB patients were classified into five phases: immune-tolerant (IT, n = 108), immune-clearance (IC, n = 161), hepatitis B e antigen negative hepatitis (ENH, n = 149), low-replicative (LR, n = 135), and liver cirrhosis (LC, n = 70). HBsAg was quantified (Abbott ARCHITECT assay) and correlated with hepatitis B virus (HBV) DNA, and serum alanine aminotransferase/aspartate aminotransferase (ALT/AST) in each phase of CHB was also determined.
RESULTS: Median HBsAg titers were different in each phase of CHB (P < 0.001): IT (4.85 log10 IU/mL), IC (4.36 log10 IU/mL), ENH (2.95 log10 IU/mL), LR (3.18 log10 IU/mL) and LC (2.69 log10 IU/mL). HBsAg titers were highest in the IT phase and lowest in the LC phase. Serum HBsAg titers showed a strong correlation with HBV viral load in the IC phase (r = 0.683, P < 0.001). No correlation between serum HBsAg level and ALT/AST was observed.
CONCLUSION: The mean baseline HBsAg levels differ significantly during the five phases of CHB, providing evidence on the natural history of HBV infection. HBsAg quantification may predict the effects of immune-modulator or oral nucleos(t)ide analogue therapy.
PMCID: PMC4112899  PMID: 25083092
Hepatitis B surface antigen quantification; Chronic hepatitis B; Natural history; Perspective
20.  Nitrosative Stress Induces Peroxiredoxin 1 Ubiquitination During Ischemic Insult via E6AP Activation in Endothelial Cells Both In Vitro and In Vivo 
Aims: Although there is accumulating evidence that increased formation of reactive nitrogen species in cerebral vasculature contributes to the progression of ischemic damage, but the underlying molecular mechanisms remain elusive. Peroxiredoxin 1 (Prx1) can initiate the antioxidant response by scavenging free radicals. Therefore, we tested the hypothesis that Prx1 regulates the susceptibility to nitrosative stress damage during cerebral ischemia in vitro and in vivo. Results: Proteomic analysis in endothelial cells revealed that Prx1 was upregulated after stress-related oxygen–glucose deprivation (OGD). Although peroxynitrite upregulated Prx1 rapidly, this was followed by its polyubiquitination within 6 h after OGD mediated by the E3 ubiquitin ligase E6-associated protein (E6AP). OGD colocalized E6AP with nitrotyrosine in endothelial cells. To assess translational relevance in vivo, mice were studied after middle cerebral artery occlusion (MCAO). This was accompanied by Prx1 ubiquitination and degradation by the activation of E6AP. Furthermore, brain delivery of a lentiviral vector encoding Prx1 in mice inhibited blood–brain barrier leakage and neuronal damage significantly following MCAO. Innovation and Conclusions: Nitrosative stress during ischemic insult activates E6AP E3 ubiquitin ligase that ubiquitinates Prx1 and subsequently worsens cerebral damage. Thus, targeting the Prx1 antioxidant defense pathway may represent a novel treatment strategy for neurovascular protection in stroke. Antioxid. Redox Signal. 21, 1–16.
PMCID: PMC4048580  PMID: 24295341
21.  Effect of Auditory Constraints on Motor Performance Depends on Stage of Recovery Post-Stroke 
In order to develop evidence-based rehabilitation protocols post-stroke, one must first reconcile the vast heterogeneity in the post-stroke population and develop protocols to facilitate motor learning in the various subgroups. The main purpose of this study is to show that auditory constraints interact with the stage of recovery post-stroke to influence motor learning. We characterized the stages of upper limb recovery using task-based kinematic measures in 20 subjects with chronic hemiparesis. We used a bimanual wrist extension task, performed with a custom-made wrist trainer, to facilitate learning of wrist extension in the paretic hand under four auditory conditions: (1) without auditory cueing; (2) to non-musical happy sounds; (3) to self-selected music; and (4) to a metronome beat set at a comfortable tempo. Two bimanual trials (15 s each) were followed by one unimanual trial with the paretic hand over six cycles under each condition. Clinical metrics, wrist and arm kinematics, and electromyographic activity were recorded. Hierarchical cluster analysis with the Mahalanobis metric based on baseline speed and extent of wrist movement stratified subjects into three distinct groups, which reflected their stage of recovery: spastic paresis, spastic co-contraction, and minimal paresis. In spastic paresis, the metronome beat increased wrist extension, but also increased muscle co-activation across the wrist. In contrast, in spastic co-contraction, no auditory stimulation increased wrist extension and reduced co-activation. In minimal paresis, wrist extension did not improve under any condition. The results suggest that auditory task constraints interact with stage of recovery during motor learning after stroke, perhaps due to recruitment of distinct neural substrates over the course of recovery. The findings advance our understanding of the mechanisms of progression of motor recovery and lay the foundation for personalized treatment algorithms post-stroke.
PMCID: PMC4066443  PMID: 25002859
bimanual movements; upper extremity; rehabilitation; motor learning/training; electromyography; task specificity; cerebrovascular disorders
22.  Immunogenicity and Tolerability to Human Papillomavirus-like Particle Vaccine in Girls and Young Women with Inflammatory Bowel Disease 
Inflammatory bowel diseases  2013;19(7):1441-1449.
Female patients receiving immunosuppressive therapy may be at increased risk for human papillomavirus (HPV) infection and cervical neoplasia.
We administered the 3-dose HPV vaccine Gardasil® to 37 females aged 9-26 years with inflammatory bowel disease (IBD) prescribed immunosuppressive therapy (prospective cohort). Geometric mean titers (GMT) in milli-Merck (mMu/mL) units were determined before dose 1 and one month after dose 3 by competitive Luminex immunoassay (cLIA) and qualitatively compared to healthy females of similar age from Merck’s database. Side effects and adverse events were evaluated. Concurrently, in 15 similar IBD patients previously vaccinated by their primary care provider we assessed antibody titers by cLIA and total IgG LIA after dose 3 of vaccine (range 0.5 to 27 months).
The mean age of prospective patients was 15 years with 51% on anti-TNF therapy and 49% on immunomodulators: 33 of 37 completed all three doses. Seropositivity after dose 3 was 100% for types 6, 11 and 16 and 96% for type 18. GMT for HPV 6, 11, 16 and 18 was 1080, 1682, 3975 and 858, respectively, and did not qualitatively differ from healthy females. No serious adverse events were attributable to the vaccine. In the previously vaccinated cohort, seropositivity was 100% for types 6, 11, and 16, and 40% for type 18 by cLIA (93% for HPV18 by IgG LIA). Titers decreased with time since dose 3.
In this small study of IBD patients prescribed immunosuppressive therapy, Gardasil® was immunogenic and there were no clinically significant vaccine-associated adverse events.
PMCID: PMC3677764  PMID: 23567780
inflammatory bowel disease; immunosuppressive therapy; human papillomavirus vaccine; immunogenicity; girls and young women
23.  Immunizations in Children with Inflammatory Bowel Disease Treated with Immunosuppressive Therapy 
Gastroenterology & Hepatology  2014;10(6):355-363.
The vast majority of patients with inflammatory bowel disease (IBD) will receive immunosuppressive therapy at some point for their disease, whether for the short term (such as a course of corticosteroids) or long term (such as maintenance therapy with immunomodulators or biologics). The systemic immunosuppression places patients at increased risk for infections. Therefore, it is important that patients are up-to-date with immunizations to minimize vaccine-preventable infections. However, the literature shows that the rate of immunization in patients with IBD is low. Ideally, the vaccination status is checked at diagnosis, and patients are immunized with the vaccines they need. Drawing titers is helpful in cases in which vaccination history is unclear or to confirm that titers are at an adequate level in cases in which patients have been vaccinated. Current guidelines recommend that patients with IBD follow the same routine immunization schedule as healthy children, but patients should not be administered live vaccines if they are receiving immunosuppressive therapy. Therefore, it is ideal to administer any necessary vaccinations as early as possible, prior to starting immunosuppressive therapy. Patients may receive inactivated vaccines regardless of immunosuppressive status. The IBD literature suggests that inactivated vaccines are safe and do not worsen disease activity. In general, patients with IBD mount an immune response to vaccines, but the response may be lower if patients are receiving immunosuppressive therapy, especially tumor necrosis factor inhibitors.
PMCID: PMC4080872  PMID: 25013388
Inflammatory bowel disease; Crohn’s disease; ulcerative colitis; vaccine; immunization; immunosuppression
24.  Proteins induced by telomere dysfunction are associated with human IgA nephropathy* #  
Aging is one of the contributing risk factors for kidney diseases. Accumulating evidence prompts the view that telomere length in kidney tissue cells is an indicator for organismal aging. Previously identified aging markers (cathelin-related antimicrobial peptide (CRAMP), stathmin, elongation factor-1α (EF-1α), and chitinase) were associated not only with telomere driven aging in mice but also with human aging and chronic diseases. This study focuses on the relationship between these biomarkers and IgA nephropathy (IgAN) progression in the Chinese population. For 260 individuals, the four markers are determined in blind datasets using direct enzyme-linked immunosorbent assay (ELISA) and immunofluorescence staining. The expression levels of CRAMP and chitinase increased in blood plasma, urine, and kidney tissues during human IgAN progression. And for the other nephropathy, such as systemic lupus erythematosus (SLE), diabetic nephropathy (DN), and focal segmental glomerulosclerosis (FSGS), there is no protein upregulation with telomere shortening. Moreover, a combination of CRAMP and chitinase can distinguish patients with IgAN from healthy individuals with 88.2%/92.5% (plasma) and 74.3%/84.2% (urine) sensitivity/specificity. These data provide the experimental evidence that telomere shortening and related inflammatory proteins are associated with human IgAN, and it could be a new direction for the disease progression study.
PMCID: PMC4116860  PMID: 24903994
Biomarkers; Telomere; IgA nephropathy (IgAN)
25.  Bleomycin-Induced Flagellate Erythema 
Balkan medical journal  2014;31(2):189-190.
PMCID: PMC4115927  PMID: 25207196

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