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1.  Optimization of the Performance of Segmented Scintillators for Radiotherapy Imaging through Novel Binning Techniques 
Physics in medicine and biology  2014;59(4):797-818.
Thick, segmented crystalline scintillators have shown increasing promise as replacement x-ray converters for the phosphor screens currently used in active matrix flat-panel imagers (AMFPIs) in radiotherapy, by virtue of providing over an order of magnitude improvement in the DQE. However, element-to-element misalignment in current segmented scintillator prototypes creates a challenge for optimal registration with underlying AMFPI arrays, resulting in degradation of spatial resolution. To overcome this challenge, a methodology involving the use of a relatively high resolution AMFPI array in combination with novel binning techniques is presented. The array, which has a pixel pitch of 0.127 mm, was coupled to prototype segmented scintillators based on BGO, LYSO and CsI:Tl materials, each having a nominal element-to-element pitch of 1.016 mm and thickness of ~1 cm. The AMFPI systems incorporating these prototypes were characterized at a radiotherapy energy of 6 MV in terms of MTF, NPS, DQE, and reconstructed images of a resolution phantom acquired using a cone-beam CT geometry. For each prototype, the application of 8×8 pixel binning to achieve a sampling pitch of 1.016 mm was optimized through use of an alignment metric which minimized misregistration and thereby improved spatial resolution. In addition, the application of alternative binning techniques that exclude the collection of signal near septal walls resulted in further significant improvement in spatial resolution for the BGO and LYSO prototypes, though not for the CsI:Tl prototype due to the large amount of optical cross-talk resulting from significant light spread between scintillator elements in that device. The efficacy of these techniques for improving spatial resolution appears to be enhanced for scintillator materials that exhibit mechanical hardness, high density and high refractive index, such as BGO. Moreover, materials that exhibit these properties as well as offer significantly higher light output than BGO, such as CdWO4, should provide the additional benefit of preserving DQE performance.
PMCID: PMC4061715  PMID: 24487347
Megavoltage cone-beam CT; flat-panel imager; electronic portal imaging device; segmented crystalline scintillators; high x-ray detection efficiency
2.  A microtubule-associated zinc finger protein, BuGZ, regulates mitotic chromosome alignment by ensuring Bub3 stability and kinetochore targeting 
Developmental cell  2014;28(3):268-281.
Equal chromosome segregation requires proper assembly of many proteins, including Bub3, onto kinetochores to promote kinetochore-microtubule interactions. By screening for mitotic regulators in the Spindle envelope and matrix (Spemix), we identify a conserved Bub3 interacting and GLEBS containing ZNF207 (BuGZ) that associates with spindle microtubules and regulates chromosome alignment. Using its conserved GLE-2-Binding Sequence (GLEBS), BuGZ directly binds and stabilizes Bub3. BuGZ also uses its microtubule-binding domain to enhance the loading of Bub3 to kinetochores that have assumed initial interactions with microtubules in prometaphase. This enhanced Bub3 loading is required for proper chromosome alignment and metaphase to anaphase progression. Interestingly, we show that microtubules are required for the highest kinetochore loading of Bub3, BubR1, and CENP-E during prometaphase. These findings suggest that BuGZ not only serves as a molecular chaperone for Bub3 but also enhances its loading onto kinetochores during prometaphase in a microtubule-dependent manner to promote chromosome alignment.
PMCID: PMC3927447  PMID: 24462186
Mitosis; microtubules; spindle envelope and matrix (Spemix); kinetochore; Bub3; BuGZ; ZFP207; ZNF207
3.  Monitoring Dynamic Glycosylation in Vivo Using Supersensitive Click Chemistry 
Bioconjugate Chemistry  2014;25(4):698-706.
To monitor the kinetics of biological processes that take place within the minute time scale, simple and fast analytical methods are required. In this article, we present our discovery of an azide with an internal Cu(I)-chelating motif that enabled the development of the fastest protocol for Cu(I)-catalyzed azide–alkyne cycloaddition (CuAAC) to date, and its application toward following the dynamic process of glycan biosynthesis. We discovered that an electron-donating picolyl azide boosted the efficiency of the ligand-accelerated CuAAC 20–38-fold in living systems with no apparent toxicity. With a combination of this azide and BTTPS, a tris(triazolylmethyl)amine-based ligand for Cu(I), we were able to detect newly synthesized cell-surface glycans by flow cytometry using as low as 1 nM of a metabolic precursor. This supersensitive chemistry enabled us to monitor the dynamic glycan biosynthesis in mammalian cells and in early zebrafish embryogenesis. In live mammalian cells, we discovered that it takes approximately 30–45 min for a monosaccharide building block to be metabolized and incorporated into cell-surface glycoconjugates. In zebrafish embryos, the labeled glycans could be detected as early as the two-cell stage. To our knowledge, this was the first time that newly synthesized glycans were detected at the cleavage period (0.75–2 hpf) in an animal model using bioorthogonal chemistry.
PMCID: PMC3993875  PMID: 24499412
4.  Characterization of Ring-Like F-Actin Structure as a Mechanical Partner for Spindle Positioning in Mitosis 
PLoS ONE  2014;9(10):e102547.
Proper spindle positioning and orientation are essential for accurate mitosis which requires dynamic interactions between microtubule and actin filament (F-actin). Although mounting evidence demonstrates the role of F-actin in cortical cytoskeleton dynamics, it remains elusive as to the structure and function of F-actin-based networks in spindle geometry. Here we showed a ring-like F-actin structure surrounding the mitotic spindle which forms since metaphase and maintains in MG132-arrested metaphase HeLa cells. This cytoplasmic F-actin structure is relatively isotropic and less dynamic. Our computational modeling of spindle position process suggests a possible mechanism by which the ring-like F-actin structure can regulate astral microtubule dynamics and thus mitotic spindle orientation. We further demonstrated that inhibiting Plk1, Mps1 or Myosin, and disruption of microtubules or F-actin polymerization perturbs the formation of the ring-like F-actin structure and alters spindle position and symmetric division. These findings reveal a previously unrecognized but important link between mitotic spindle and ring-like F-actin network in accurate mitosis and enables the development of a method to theoretically illustrate the relationship between mitotic spindle and cytoplasmic F-actin.
PMCID: PMC4191959  PMID: 25299690
5.  The Responsivity of a Miniaturized Passive Implantable Wireless Pressure Sensor 
A miniature batteryless implantable wireless pressure sensor that can be used deep inside the body is desired by the medical community. MEMS technology makes it possible to achieve high responsivity that directly determines the operating distance between a miniature implanted sensor and the external RF probe, while providing the read-out. In this paper, for the first time, an analytical expression of the system responsivity versus the sensor design is derived using an equivalent circuit model. Also, the integration of micro-coil inductors and pressure sensitive capacitors on a single silicon chip using MEMS fabrication techniques is demonstrated. Further, the derived analytical design theory is validated by the measured responsivity of these sensors.
PMCID: PMC4189120  PMID: 25309965
6.  Synthesis and Biological Evaluation of Novel N-phenyl-5-carboxamidyl Isoxazoles as Potential Chemotherapeutic Agents for Colon Cancer 
A new series of isoxazole derivatives, N-phenyl-5-carboxamidyl isoxazoles, was investigated for their anticancer activity with solid tumor selectivity. Six N-phenyl-5-carboxamidylisoxazoles were chemically synthesized and evaluated by the in vitro disk-diffusion assay and IC50 cytotoxicity determination. The results showed that one of the derivatives, compound 3, N-(4-chlorophenyl)-5-carboxamidyl isoxazole, was the most active against colon 38 and CT-26 mouse colon tumor cells with an IC50 of 2.5 μg/mL for both cell lines. Western blot analysis showed that compound 3 significantly down-regulated the expression of phosphorylated STAT3 in both human and mouse colon cancer cells indicating that the mechanism of action for compound 3 may involve the inhibition of JAK3/STAT3 signaling pathways. Flow cytometric analysis with Annexin V staining showed that the death induced by compound 3 is mediated through cell necrosis and not apoptotic pathway. In summary, our results show that compound 3 is a new N-phenyl-5-carboxamidyl isoxazole with potential anticancer activity. Compound 3 inhibits the phosphorylation of STAT3, a novel target for chemotherapeutic drugs, and is worthy of further investigation as a potential chemotherapeutic agent for treating colon cancer.
PMCID: PMC4182953  PMID: 25285182
7.  Obesity Affects the Biopsy-Mediated Detection of Prostate Cancer, Particularly High-Grade Prostate Cancer: A Dose-Response Meta-Analysis of 29,464 Patients 
PLoS ONE  2014;9(9):e106677.
Background and Objectives
In previous studies, obesity (measured according to the body mass index) has correlated inconsistently with the risk of biopsy-measured prostate cancer, and specifically high-grade prostate cancer. This meta-analysis aimed to clarify these correlations.
A comprehensive literature search of the MEDLINE and EMBASE databases was conducted for relevant studies published through January 2014. The pooled estimates of odds ratios (OR) and confidence intervals (CI) were computed, and the meta-analysis was performed with the STATA software according to a random effects approach.
A total of 11 studies that included 29,464 individuals were identified. A 5-kg/m2 increase in body mass index was associated with a 15% (OR, 1.15; 95% CI, 0.98–1.34) higher risk of prostate cancer detection and a 37% (OR, 1.37; 95% CI, 1.19–1.57) higher risk of high-grade prostate cancer detection at biopsy. There were no differences among the results of studies conducted in the USA, Europe or Asia. We also found that studies that had adjusted for prostate-specific antigen levels, digital rectal examination results, and prostate volumes obtained positive significant outcomes (OR, 1.27; 95% CI, 1.12–1.44), whereas studies that did not adjust for the above-mentioned confounding variables obtained negative results (OR, 0.92; 95% CI, 0.68–1.25). Moreover, the positive correlation between body mass index and the detection of both prostate cancer and high-grade diseases tended to be stronger as the number of biopsy cores increased.
The present meta-analysis demonstrated that a high body mass index correlated positively with prostate cancer detection, especially high-grade prostate cancer detection. The adoption of a modified and possibly more aggressive biopsy strategy was suggested for obese populations.
PMCID: PMC4153672  PMID: 25184215
8.  Intensity of stromal changes is associated with tumor relapse in clinically advanced prostate cancer after castration therapy 
Asian Journal of Andrology  2014;16(5):710-714.
Reactive stromal changes in prostate cancer (PCa) are likely involved in the emergence of castration-resistant PCa (CRPC). This study was designed to investigate stromal changes in patients with clinically advanced PCa and analyze their prognostic significance. Prostate needle biopsies obtained from 148 patients before castration therapy were analyzed by Masson trichrome staining and immunohistochemical analysis of vimentin and desmin. Reactive stroma grading was inversely correlated with Gleason score. Stroma grade (Masson stain 82.8% vs 45.6%, P < 0.001) and vimentin expression (P = 0.005) were significantly higher, and desmin expression (P = 0.004) significantly lower, in reactive stroma of tumors with a Gleason score of 6–7 than in adjacent peritumoral tissue. Kaplan-Meier analysis showed a significant association between reactive stroma grade in tumors and the occurrence of CRPC in patients with a Gleason score of 6–7 (P = 0.009). Furthermore, patients with higher vimentin or lower desmin expression had a shorter disease-free period. In multivariate analysis, only vimentin expression was a significant predictor of tumor relapse (hazard ratio 1.78, 95% confidence interval 1.12–10.26, P = 0.012). These findings indicate that the intensity of reactive stroma is associated with castration responsiveness, especially in patients with a lower Gleason score where the abundant stroma component is most frequently found. High expression of vimentin in tumor stroma was independently associated with poor outcomes in patients with Gleason scores of 6–7, and may serve as a new prognostic marker in daily practice.
PMCID: PMC4215666  PMID: 24875819
cancer-associated fibroblasts; castration resistance; prostate cancer; reactive stroma; vimentin
9.  Fewer complications after laparoscopic nephrectomy as compared to the open procedure with the modified Clavien classification system - a retrospective analysis from Southern China 
The objective of the study is to compare complication rates of laparoscopic nephrectomy and open nephrectomy using a standardized classification method
We retrospectively included 843 patients from March 2006 to November 2012, of whom 88 had laparoscopic radical nephrectomy (LRN), 526 had open radical nephrectomy (ORN), 42 had laparoscopic partial nephrectomy (LPN), and 187 had open partial nephrectomy (OPN). A modified Clavien classification system was applied to quantify complications of nephrectomy. Fisher’s exact or chi-square test were used to compare complication rates between laparoscopic and open approaches.
The overall complication rate was 19.31%, 30.04%, 35.71%, and 36.36% in LRN, ORN, LPN, and OPN, respectively. More Grade II complications (odds ratio = 2.593, 95% CI 1.172 to 5.737, P = 0.010) and longer postoperation hospital stay (9.2 days and 7.6 days, P < 0.001) were observed in ORN compared with LRN. In multivariable analysis, surgical approach (LRN/ORN) (P = 0.036), age (P = 0.044), height (P = 0.020), systolic pressure (P = 0.012), fasting blood glucose level (P = 0.032), and blood loss during operation (P = 0.011) were significant predictors for grade II complications in radical nephrectomy. LPN had similar complication rates compared with OPN.
In conclusion, LRN had the advantages of less grade II complications and shorter postoperation hospital stay than ORN. Older age and more blood loss during operation would also contribute to more grade II complications in radical nephrectomy.
PMCID: PMC4121009  PMID: 25081928
Clavien classification system; Complication; Laparoscopy; Nephrectomy
10.  Subanesthetic Isoflurane Reduces Zymosan-Induced Inflammation in Murine Kupffer Cells by Inhibiting ROS-Activated p38 MAPK/NF-κB Signaling 
Volatile anesthetic isoflurane (ISO) has immunomodulatory effects. The fungal component zymosan (ZY) induces inflammation through toll-like receptor 2 or dectin-1 signaling. We investigated the molecular actions of subanesthetic (0.7%) ISO against ZY-induced inflammatory activation in murine Kupffer cells (KCs), which are known as the resident macrophages within the liver. We observed that ISO reduced ZY-induced cyclooxygenase 2 upregulation and prostaglandin E2 release, as determined by western blot and radioimmunoassay, respectively. ISO also reduced the production of tumor necrosis factor-α, interleukin-1β, IL-6, high-mobility group box-1, macrophage inflammatory protein-1α, macrophage inflammatory protein-2, and monocyte chemoattractant protein-1 as assessed by enzyme-linked immunosorbent assays. ISO blocked the ZY-induced nuclear translocation and DNA-binding activity of nuclear factor- (NF)-κB p65. Moreover, ISO attenuated ZY-induced p38 mitogen-activated protein kinase (MAPK) activation partly by scavenging reactive oxygen species (ROS); the interregulation that ROS activated p38 MAPK followed by NF-κB activation was crucial for the ZY-induced inflammatory responses in KCs. An in vivo study by peritoneal injection of ZY into BALB/C mice confirmed the anti-inflammatory properties of 0.7% ISO against ZY in KCs. These results suggest that ISO ameliorates ZY-induced inflammatory responses in murine KCs by inhibiting the interconnected ROS/p38 MAPK/NF-κB signaling pathways.
PMCID: PMC4134815  PMID: 25147596
11.  Helicobacter pylori infection promotes the invasion and metastasis of gastric cancer through increasing the expression of matrix metalloproteinase-1 and matrix metalloproteinase-10 
The aim of this study was to investigate the effect and mechanism of Helicobacter pylori infection in the invasion and metastasis of gastric cancer. Specimens from 80 patients with gastric cancer (of which 20 patients had metastatic gastric cancer) and 40 patients with chronic gastritis were included in this study. H. pylori infection was determined by ELISA and the expression of matrix metalloproteinase-1 (MMP-1) and MMP-10 was observed using immunohistochemistry. The correlation between H. pylori infection and the clinical pathological features of gastric cancer was analyzed by SPSS 13.0 software. The protein expression levels of MMP-1 and MMP-10 in MGC-803 cells infected with H. pylori were analyzed using western blotting. H. pylori infection was found in 62 of the 80 patients with gastric cancer and in 13 of the 40 patients with chronic gastritis. In addition, H. pylori infection was correlated with the staging and lymph node metastasis, but not with the gender, age and histological types of patients. H. pylori infection was also significantly correlated with the expression of MMP-1 and MMP-10 (r=0.8718, P<0.05 and r=0.5477, P<0.05, respectively). The expression of MMP-1 and MMP-10 was significantly upregulated following induction by H. pylori infection (P<0.05), with significant effects occurring following infection for 12 and 6 h, respectively. H. pylori infection may promote the invasion and metastasis of gastric cancer by increasing the expression of MMP-1 and MMP-10.
PMCID: PMC4113550  PMID: 25120597
gastric cancer; Helicobacter pylori; matrix metalloproteinase-1; matrix metalloproteinase-10; metastasis
12.  Single-stranded DNA as a Cleavable Linker for Bioorthogonal Click Chemistry-based Proteomics 
Bioconjugate chemistry  2013;24(6):859-864.
In this report, we present a new class of cleavable linker based on automatically synthesized, single-stranded DNAs. We incorporated a DNA oligo into an azide-functionalized biotin (biotin-DNA-N3) and used the probe to enrich alkyne-tagged glycoproteins from mammalian cell lysates. Highly efficient and selective release of the captured proteins from streptavidin agarose resins was achieved using DNase treatment under very mild conditions. A total of 36 sialylated glycoproteins were identified from the lysates of HL60 cells, an acute human promyeloid leukemia cell line. These sialylated glycoproteins were involved in many different biological processes ranging from glycan biosynthesis to cell adhesion events.
PMCID: PMC4078914  PMID: 23627610
13.  Down-Regulation of CD9 by Methylation Decreased Bortezomib Sensitivity in Multiple Myeloma 
PLoS ONE  2014;9(5):e95765.
Bortezomib therapy has been proven successful for the treatment of relapsed and/or refractory multiple myeloma (MM). However, both intrinsic and acquired resistance has already been observed. In this study, we explored the relationship between CD9 expression and bortezomib sensitivity in MM. We found that down-regulation of CD9 by methylation decreased bortezomib sensitivity in multiple myeloma. CD9 expression obviously increased bortezomib sensitivity through inducing apoptosis, significantly inhibiting U266 cells' adhesion to HS-5 and primary bone marrow stromal cells, but increasing U266 cells' adhesion to fibronectin. CD9 expression also significantly inhibited U266 cell migration. The mechanisms may include: the endoplasmic reticulum stress pathway, cell adhesion related signaling pathway and osteoclast differentiation related signaling pathway. Combination therapy with de-methylation reagent 5-Aza-2-deoxycytidine may prove useful to the development of novel strategies for the treatment of bortezomib-resistant MM patients.
PMCID: PMC4008425  PMID: 24788635
14.  The influence of prostate volume on cancer detection in the Chinese population 
Asian Journal of Andrology  2014;16(3):482-486.
In western populations, prostate volume (PV) has been proven to be one of the strongest predictors of detecting prostate cancer (PCa) in biopsies. We performed this study in a biopsy cohort, to evaluate associations among the prostate volume, prostate-specific antigen (PSA) and PCa detection in the Chinese population. Between the years, 2007–13, 1486 men underwent prostate biopsy at Huashan Hospital, Fudan University, Shanghai, China. The study population was divided into two groups for analysis according to total PSA (tPSA) range (4 ng ml−1 < tPSA ≤20 ng ml−1 and tPSA > 20 ng ml−1). PV, age, tPSA, digital rectal examination (DRE) and transrectal ultrasound (TRUS) results were also included in the analysis. Although the positive biopsy rates decreased in both tPSA range groups, the downtrend was more pronounced in the 4 ng ml−1 < tPSA ≤20 ng ml−1 group; therefore, we focused on 853 men in this group with increasing PV. In multivariate logistic regression analysis, only DRE was found to be associated with PCa in four PV groups (P < 0.05) and tPSA did not show a good predictive ability when PV exceeded 50 ml (P > 0.05). Further, it may suggest that with increasing PV, the cancer detection rate decreased in men with different tPSA, DRE and TRUS nodule statuses (all P values for trends were <0.001). Our study indicates that in tPSA ranging from 4 to 20 ng ml−1, the use of PV ranges of 0–35 ml, 35–50 ml and > 50 ml might be taken into consideration for the biopsy decision-making in the Chinese population.
PMCID: PMC4023383  PMID: 24625884
China; prostate cancer; prostate-specific antigen; prostate volume
15.  A New Chiral Pyrrolyl α-Nitronyl Nitroxide Radical Attenuates β-Amyloid Deposition and Rescues Memory Deficits in a Mouse Model of Alzheimer Disease 
Neurotherapeutics  2012;10(2):340-353.
The generation of reactive oxygen species causes cellular oxidative damage, and has been implicated in the etiology of Alzheimer’s disease (AD). L-NNNBP, a new chiral pyrrolyl α-nitronyl nitroxide radical synthesized in our department, shows potential antioxidant effects. The purpose of this study was to investigate the protective effects of L-NNNBP on β-amyloid (Aβ) deposition and memory deficits in an AD model of APP/PS1 mice. In cultured cortical neurons, L-NNNBP acted as an antioxidant by quenching reactive oxygen species, inhibiting lipid peroxidation, nitrosative stress, and stimulating cellular antioxidant defenses. L-NNNBP inhibited cell apoptosis induced by Aβ exposure. In vivo treatment with L-NNNBP for 1 month induced a marked decrease in brain Aβ deposition and tau phosphorylation in the blinded study on APP/PS1 transgenic mice (1 mM in drinking water, initiated when the mice were 6 months old). The L-NNNBP-treated APP/PS1 mice showed decreased astrocyte activation and improved spatial learning and memory compared with the vehicle-treated APP/PS1 mice. These actions were more potent compared with that of curcumin, a natural product, and TEMPO, a nitroxide radical, which are used as free radical scavengers in clinics. These results proved that the newly synthesized L-NNNBP was an effective therapeutic agent for the prevention and treatment of AD.
Electronic supplementary material
The online version of this article (doi:10.1007/s13311-012-0168-z) contains supplementary material, which is available to authorized users.
PMCID: PMC3625382  PMID: 23212232
Reactive oxygen species; Alzheimer disease; Nitroxide radical; L-NNNBP; β-amyloid
16.  Regulation of transcription by the MLL2 complex and MLL complex-associated AKAP95 
Nature structural & molecular biology  2013;20(10):10.1038/nsmb.2656.
Although histone H3 lysine 4 (H3K4) methylation is widely associated with gene activation, direct evidence for its causal role in transcription, through specific MLL family members, is scarce. Here we have purified a human MLL2 (Kmt2b) complex that is highly active in H3K4 methylation and chromatin transcription in a cell-free system. This effect requires SAM and intact H3K4, establishing a direct and causal role for MLL2-mediated H3K4 methylation in transcription. We then show that human AKAP95, a chromatin-associated protein, is physically and functionally associated with the DPY30–MLL complexes and directly enhances their methyltransferase activity. Ectopic AKAP95 stimulates expression of a chromosomal reporter in synergy with MLL1 or MLL2, whereas AKAP95 depletion impairs retinoic acid-mediated gene induction in embryonic stem cells. These results demonstrate an important role for AKAP95 in regulating histone methylation and gene expression, particularly during cell fate transitions.
PMCID: PMC3813012  PMID: 23995757
17.  Effect of Paris saponin I on radiosensitivity in a gefitinib-resistant lung adenocarcinoma cell line 
Oncology Letters  2014;7(6):2059-2064.
Previous studies have observed that Paris saponin I (PSI) exerts a wide range of pharmacological activities, including cytotoxic activity against a number of malignancies, such as non-small cell lung cancers. The present study aimed to investigate the radiosensitization of PSI treatment on a gefitinib-resistant lung adenocarcinoma cell line, PC-9-ZD, and its possible mechanism. A 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl-tetrazolium bromide assay was used to determine the growth inhibition effect of PSI. A clonogenic assay was performed to determine the radiosensitizing effect of PSI treatment on the PC-9-ZD cell line. A single-hit multi-target model was used to plot survival curves and calculate sensitizing enhancement ratios. The cell cycle was analyzed by flow cytometry and cell apoptosis was analyzed with fluorescein-isothiocyanate-Annexin V/propidium iodide and Hoechst staining. The expression levels of the proteins were detected by western blotting. There was a significant reduction observed in the proliferation of the PC-9-ZD cell lines that were treated with PSI. PSI enhanced the radiosensitivity of the PC-9-ZD cells with a sensitization enhancement ratio of 1.77. Furthermore, PSI induced G2/M arrest and apoptosis of the irradiated PC-9-ZD cells. Notably, B-cell lymphoma 2 (Bcl-2) was downregulated, and caspase-3, Bcl-2-like protein 4 (Bax) and cyclin-dependent kinase inhibitor 1 (P21waf1/cip1) were upregulated by the PSI treatment. The present study showed that PSI treatment exhibited potent radiosensitivity against gefitinib-resistant PC-9-ZD cells in vitro. This radiosensitivity was associated with cell cycle arrest at the G2/M phase, and apoptosis via an increase in caspase-3, Bax and P21waf1/cip1 as well as a decrease in Bcl-2 production.
PMCID: PMC4049680  PMID: 24932289
radiosensitivity; clonogenic cell survival; Paris saponin I; gefitinib resistance
18.  Multimodal Neuroprotection Induced by PACAP38 in Oxygen–Glucose Deprivation and Middle Cerebral Artery Occlusion Stroke Models 
Pituitary adenylate cyclase activating peptide (PACAP), a potent neuropeptide which crosses the blood–brain barrier, is known to provide neuroprotection in rat stroke models of middle cerebral artery occlusion (MCAO) by mechanism(s) which deserve clarification. We confirmed that following i.v. injection of 30 ng/kg of PACAP38 in rats exposed to 2 h of MCAO focal cerebral ischemia and 48 h reoxygenation, 50 % neuroprotection was measured by reduced caspase-3 activity and volume of cerebral infarction. Similar neuroprotective effects were measured upon PACAP38 treatment of oxygen–glucose deprivation and reoxygenation of brain cortical neurons. The neuroprotection was temporally associated with increased expression of brain-derived neurotrophic factor, phosphorylation of its receptor—tropomyosin-related kinase receptor type B (trkB), activation of phosphoinositide 3-kinase and Akt, and reduction of extracellular signal-regulated kinases 1/2 phosphorylation. PACAP38 increased expression of neuronal markers beta-tubulin III, microtubule-associated protein-2, and growth-associated protein-43. PACAP38 induced stimulation of Rac and suppression of Rho GTPase activities. PACAP38 down-regulated the nerve growth factor receptor (p75NTR) and associated Nogo-(Neurite outgrowth-A) receptor. Collectively, these in vitro and in vivo results propose that PACAP exhibits neuroprotective effects in cerebral ischemia by three mechanisms: a direct one, mediated by PACAP receptors, and two indirect, induced by neurotrophin release, activation of the trkB receptors and attenuation of neuronal growth inhibitory signaling molecules p75NTR and Nogo receptor.
PMCID: PMC3955207  PMID: 22678884
Stroke; Apoptosis; Neuroprotection; PACAP; BDNF; trkB; p75; NgR; Akt; Erk1/2
19.  Effects of bone cement on intervertebral disc degeneration 
Percutaneous vertebroplasty (PVP) is popular for the treatment of intractable pain due to vertebral collapse from various lesions, intervertebral disk leakage of cement is a frequent complication. The aim of this study was to determine whether bone cement causes disc degeneration, and to evaluate the degree of intervertebral disc degeneration (IDD) according to the time period following cement injection, and the type and volume of cement injected. Sixteen dogs were randomly divided into two groups that were sacrificed at 12 or 24 weeks following cement injection. Five intervertebral discs in each dog were studied, including one control untreated disc and four discs randomly injected with polymethylmethacrylate (PMMA) or calcium phosphate cement (CPC) in two quantities. Radiographic and magnetic resonance imaging (MRI) studies were performed prior to animal sacrifice. T2-weighted mid-sagittal images of the discs were qualitatively analyzed for evidence of degeneration by calculating the MRI index, and all harvested discs were studied histopathologically. IDD was not evident in control discs. Univariate analysis revealed significant differences in the MRI index and the histological grade of disc degeneration in terms of the time period following cement injection, as well as the type and volume of cement injected. Result indicate that direct contact with PMMA and CPC can lead to IDD. However, IDD induced by PMMA was more severe than that induced by CPC. The extent of IDD was found to correlate with the time period post-cement injection and the volume of cement injected into the disc. PMMA and CPC may lead to intervertebral disc degeneration. Intervertebral disc degeneration induced by PMMA is more serious than that of CPC. The degree of intervertebral disc degeneration is correlative to the time after operation and the doses of bone cement.
PMCID: PMC3965156  PMID: 24669259
vertebroplasty; polymethyl methacrylate; calcium phosphate cement; intervertebral disc; degeneration; magnetic resonance imaging
20.  Development of active matrix flat panel imagers incorporating thin layers of polycrystalline HgI2 for mammographic x-ray imaging 
Physics in medicine and biology  2013;58(3):703-714.
Active matrix flat-panel imagers (AMFPIs) offer many advantages and have become ubiquitous across a wide variety of medical x-ray imaging applications. However, for mammography, the imaging performance of conventional AMFPIs incorporating CsI:Tl scintillators or a-Se photoconductors is limited by their relatively modest signal-to-noise ratio (SNR), particularly at low x-ray exposures or high spatial resolution. One strategy for overcoming this limitation involves the use of a high gain photoconductor such as mercuric iodide (HgI2) which has the potential to improve the signal-to-noise ratio by virtue of its low effective work function (WEFF). In this study, the performance of direct-detection AMFPI prototypes employing relatively thin layers of polycrystalline HgI2 operated under mammographic irradiation conditions over a range of 0.5 to 16.0 mR is presented. High x-ray sensitivity (corresponding to WEFF values of ~19 eV), low dark current (<0.1 pA/mm2) and good spatial resolution, largely limited by the size of the pixel pitch, were observed. For one prototype, a detective quantum efficiency of ~70% was observed at an x-ray exposure of ~0.5 mR at 26 kVp.
PMCID: PMC3620658  PMID: 23318606
Active matrix flat panel imager; polycrystalline HgI2; DQE; screen-printing
21.  Molecular Insights into the pH-Dependent Adsorption and Removal of Ionizable Antibiotic Oxytetracycline by Adsorbent Cyclodextrin Polymers 
PLoS ONE  2014;9(1):e86228.
Effects of pH on adsorption and removal efficiency of ionizable organic compounds (IOCs) by environmental adsorbents are an area of debate, because of its dual mediation towards adsorbents and adsorbate. Here, we probe the pH-dependent adsorption of ionizable antibiotic oxytetracycline (comprising OTCH2+, OTCH±, OTC−, and OTC2−) onto cyclodextrin polymers (CDPs) with the nature of molecular recognition and pH inertness. OTCH± commonly has high adsorption affinity, OTC− exhibits moderate affinity, and the other two species have negligible affinity. These species are evidenced to selectively interact with structural units (e.g., CD cavity, pore channel, and network) of the polymers and thus immobilized onto the adsorbents to different extents. The differences in adsorption affinity and mechanisms of the species account for the pH-dependent adsorption of OTC. The mathematical equations are derived from the multiple linear regression (MLR) analysis of quantitatively relating adsorption affinity of OTC at varying pH to adsorbent properties. A combination of the MLR analysis for OTC and molecular recognition of adsorption of the species illustrates the nature of the pH-dependent adsorption of OTC. Based on this finding, γ-HP-CDP is chosen to adsorb and remove OTC at pH 5.0 and 7.0, showing high removal efficiency and strong resistance to the interference of coexisting components.
PMCID: PMC3897700  PMID: 24465975
22.  Oleanane Triterpenoid CDDO-Me Inhibits Growth and Induces Apoptosis in Prostate Cancer Cells by Independently Targeting Pro-Survival Akt and mTOR 
The Prostate  2009;69(8):10.1002/pros.20937.
Synthetic triterpenoids are potent anticancer agents, but their therapeutic efficacy or mechanism of action for prostate cancer has not been investigated. The goal of this study was to determine the antitumor activity and the mechanism of action of methyl-2-cyano-3,12-dioxooleana-1,9(11)-dien-28-oate (CDDO-Me), a oleanane-derived synthetic triterpenoid for human prostate cancer cells.
The antitumor activity of CDDO-Me for hormone-refractory PC-3 (AR−) and C4-2 (AR+) prostate cancer cell lines was determined by effects on cell growth and induction of apoptosis, identification of molecular targets, and therapeutic efficacy in vivo in PC-3 xenograft model.
CDDO-Me inhibited the growth and induced apoptosis in PC-3 and C4-2 cells at extremely low concentrations. The antitumor activity of CDDO-Me was associated with the inhibition of p-Akt, mammalian target of rapamycin (mTOR), and nuclear factor kappa B (NF-κB) signaling proteins and their downstream targets such as p-Bad and p-Foxo3a (Akt); p-S6K1, p-eIF-4E and p-4E-BP1 (mTOR); and COX-2, VEGF and cyclin D1(NF-κB). Silencing of Akt sensitized the PC-3 cells to CDDO-Me, whereas overexpression of Akt induced resistance to CDDO-Me. Targeted silencing of Akt showed that Akt does not regulate mTOR activation in PC-3 cells, but targeted silencing of mTOR sensitized PC-3 cells to CDDO-Me mediated growth inhibition. Further, treatment with CDDO-Me inhibited the growth of PC-3 xenografts in nude mice.
This study demonstrated potent antitumor activity of CDDO-Me against prostate cancer cells both in vitro and in vivo. Data also identified Akt and mTOR as molecular targets of CDDO-Me in prostate cancer cells.
PMCID: PMC3865612  PMID: 19189297
CDDO-Me; prostate cancer; apoptosis; Akt; mTOR; xenograft
23.  Discovery of metabolite biomarkers: flux analysis and reaction-reaction network approach 
BMC Systems Biology  2013;7(Suppl 2):S13.
Metabolism is a vital cellular process, and its malfunction can be a major contributor to many human diseases. Metabolites can serve as a metabolic disease biomarker. An detection of such biomarkers plays a significant role in the study of biochemical reaction and signaling networks. Early research mainly focused on the analysis of the metabolic networks. The issue of integrating metabolite networks with other available biological data to reveal the mechanics of disease-metabolite associations is an important and interesting challenge.
In this article, we propose two new approaches for the identification of metabolic biomarkers with the incorporation of disease specific gene expression data and the genome-scale human metabolic network. The first approach is to compare the flux interval between the normal and disease sample so as to identify reaction biomarkers. The second one is based on the Reaction-Reaction Network (RRN) to reveal the significant reactions. These two approaches utilize reaction flux obtained by a Linear Programming (LP) based method that can contribute to the discovery of potential novel biomarkers.
Biomarker identification is an important issue in studying biochemical reactions and signaling networks. Two efficient and effective computational methods are proposed for the identification of biomarkers in this article. Furthermore, the biomarkers found by our proposed methods are shown to be significant determinants for diabetes.
PMCID: PMC3866256  PMID: 24564929
24.  Neuronal aging: learning from C. elegans 
The heterogeneity and multigenetic nature of nervous system aging make modeling of it a formidable task in mammalian species. The powerful genetics, simple anatomy and short life span of the nematode Caenorhabditis elegans offer unique advantages in unraveling the molecular genetic network that regulates the integrity of neuronal structures and functions during aging. In this review, we first summarize recent breakthroughs in the morphological and functional characterization of C. elegans neuronal aging. Age-associated morphological changes include age-dependent neurite branching, axon beading or swelling, axon defasciculation, progressive distortion of the neuronal soma, and early decline in presynaptic release function. We then discuss genetic pathways that modulate the speed of neuronal aging concordant with alteration in life span, such as insulin signaling, as well as cell-autonomous factors that promote neuronal integrity during senescence, including membrane activity and JNK/MAPK signaling. As a robust genetic model for aging, insights from C. elegans neuronal aging studies will contribute to our mechanistic understanding of human brain aging.
PMCID: PMC3895751  PMID: 24325838
C. elegans; Aging; Neurons; Neural activity; Insulin signaling
25.  Activation of transsulfuration pathway by salvianolic acid a treatment: a homocysteine-lowering approach with beneficial effects on redox homeostasis in high-fat diet-induced hyperlipidemic rats 
Elevated homocysteine is a cardiovascular risk factor in hyperlipidemia. Transsulfuration pathway provides an endogenous pathway for homocysteine conversion to antioxidant glutathione (GSH). Salvianolic acid A (Sal A) contains two molecules of caffeic acid and one molecule of danshensu that is capable of enhancing homocysteine transsulfuration, which led to the hypothesis that Sal A has activatory effect on transsulfuration pathway and this effect may have beneficial effects on both homocysteine and redox status in hyperlipidemia.
Methods and results
To test this hypothesis, we developed a rat model of hyperlipidemia induced by high-fat diet for 16 weeks, during which rats were treated with 1 mg/kg salvianolic acid A (Sal A) for the final 4 weeks. Activities of key enzymes and metabolite profiling in the transsulfuration pathway revealed that hyperlipidemia led to elevated plasma homocysteine levels after 16-week dietary treatment, which was associated with reduced activities of homocysteine transsulfuration enzymes, cystathionine β-synthase (CBS) and cystathionine γ-lyase (CSE). The impaired transsulfuration pathway prevented homocysteine transsulfuration to cysteine, resulting in cysteine deficiency and subsequent reduction in GSH pool size. The redox status was altered in the setting of hyperlipidemia as indicated by GSH/GSSG ratio. Sal A treatment increased hepatic CBS and CSE activities, which was associated with reduced accumulation in circulating homocysteine levels and attenuated decline in hepatic cysteine content in hyperlipidemic rats. Sal A also led to an increase in GSH pool size, which subsequently caused a restored GSH/GSSG ratio. The activatory effect of Sal A on CBS was also observed in normal rats and in in vitro experiment.
Our results suggest that activation of transsulfuration pathway by Sal A is a promising homocysteine-lowering approach that has beneficial effects on redox homeostasis in hyperlipidemic settings.
PMCID: PMC4028786  PMID: 24314320
Hyperlipidemia; Transsulfuration pathway; Homocysteine; Redox status; Salvianolic acid A

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