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1.  A Glimpse of Matrix Metalloproteinases in Diabetic Nephropathy 
Current medicinal chemistry  2014;21(28):3244-3260.
Matrix metalloproteinases (MMPs) are proteolytic enzymes belonging to the family of zinc-dependent endopeptidases that are capable of degrading almost all the proteinaceous components of the extracellular matrix (ECM). It is known that MMPs play a role in a number of renal diseases, such as, various forms of glomerulonephritis and tubular diseases, including some of the inherited kidney diseases. In this regard, ECM accumulation is considered to be a hallmark morphologic finding of diabetic nephropathy, which not only is related to the excessive synthesis of matrix proteins, but also to their decreased degradation by the MMPs. In recent years, increasing evidence suggest that there is a good correlation between the activity or expression of MMPs and progression of renal disease in patients with diabetic nephropathy in humans and in various experimental animal models. In such a diabetic milieu, the expression of MMPs is modulated by high glucose, advanced glycation end products (AGEs), TGF-β, reactive oxygen species (ROS), transcription factors and some of the microRNAs. In this review, we focused on the structure and functions of MMPs, and their role in the pathogenesis of diabetic nephropathy.
PMCID: PMC4281028  PMID: 25039784
Diabetic nephropathy; extracellular matrix; metalloproteinases; TGF-β
3.  Mutational analysis of Polycomb genes in solid tumours identifies PHC3 amplification as a possible cancer-driving genetic alteration 
British Journal of Cancer  2013;109(6):1699-1702.
Background:
Polycomb group genes (PcGs) are epigenetic effectors implicated in most cancer hallmarks. The mutational status of all PcGs has never been systematically assessed in solid tumours.
Methods:
We conducted a multi-step analysis on publically available databases and patient samples to identify somatic aberrations of PcGs.
Results:
Data from more than 1000 cancer patients show for the first time that the PcG member PHC3 is amplified in three epithelial neoplasms (rate: 8–35%). This aberration predicts poorer prognosis in lung and uterine carcinomas (P<0.01). Gene amplification correlates with mRNA overexpression (P<0.01), suggesting a functional role of this aberration.
Conclusion:
PHC3 amplification may emerge as a biomarker and potential therapeutic target in a relevant fraction of epithelial tumours.
doi:10.1038/bjc.2013.454
PMCID: PMC3776977  PMID: 23942079
Polycomb; lung cancer; endometrial cancer
4.  Accelerated partial-breast irradiation using intensity-modulated proton radiotherapy: do uncertainties outweigh potential benefits? 
The British Journal of Radiology  2013;86(1029):20130176.
Objective:
Passive scattering proton beam (PSPB) radiotherapy for accelerated partial-breast irradiation (APBI) provides superior dosimetry for APBI three-dimensional conformal photon radiotherapy (3DCRT). Here we examine the potential incremental benefit of intensity-modulated proton radiotherapy (IMPT) for APBI and compare its dosimetry with PSPB and 3DCRT.
Methods:
Two theoretical IMPT plans, TANGENT_PAIR and TANGENT_ENFACE, were created for 11 patients previously treated with 3DCRT APBI and were compared with PSPB and 3DCRT plans for the same CT data sets. The impact of range, motion and set-up uncertainties as well as scanned spot mismatching between fields of IMPT plans was evaluated.
Results:
IMPT plans for APBI were significantly better regarding breast skin sparing (p<0.005) and other normal tissue sparing than 3DCRT plans (p<0.01) with comparable target coverage (p=ns). IMPT plans were statistically better than PSPB plans regarding breast skin (p<0.002) and non-target breast (p<0.007) in higher dose regions but worse or comparable in lower dose regions. IMPT plans using TANGENT_ENFACE were superior to that using TANGENT_PAIR in terms of target coverage (p<0.003) and normal tissue sparing (p<0.05) in low-dose regions. IMPT uncertainties were demonstrated for multiple causes. Qualitative comparison of dose–volume histogram confidence intervals for IMPT suggests that numeric gains may be offset by IMPT uncertainties.
Conclusion:
Using current clinical dosimetry, PSPB provides excellent dosimetry compared with 3DCRT with fewer uncertainties compared with IMPT.
Advances in knowledge:
As currently delivered in the clinic, PSPB planning for APBI provides as good or better dosimetry than IMPT with less uncertainty.
doi:10.1259/bjr.20130176
PMCID: PMC3755395  PMID: 23728947
5.  Activation-induced necroptosis contributes to B-cell lymphopenia in active systemic lupus erythematosus 
Fan, H | Liu, F | Dong, G | Ren, D | Xu, Y | Dou, J | Wang, T | Sun, L | Hou, Y
Cell Death & Disease  2014;5(9):e1416-.
B-cell abnormality including excessive activation and lymphopenia is a central feature of systemic lupus erythematosus (SLE). Although activation threshold, auto-reaction and death of B cells can be affected by intrinsical and/or external signaling, the underlying mechanisms are unclear. Herein, we demonstrate that co-activation of Toll-like receptor 7 (TLR7) and B-cell receptor (BCR) pathways is a core event for the survival/dead states of B cells in SLE. We found that the mortalities of CD19+CD27- and CD19+IgM+ B-cell subsets were increased in the peripheral blood mononuclear cells (PBMCs) of SLE patients. The gene microarray analysis of CD19+ B cells from active SLE patients showed that the differentially expressed genes were closely correlated to TLR7, BCR, apoptosis, necroptosis and immune pathways. We also found that co-activation of TLR7 and BCR could trigger normal B cells to take on SLE-like B-cell characters including the elevated viability, activation and proliferation in the first 3 days and necroptosis in the later days. Moreover, the necroptotic B cells exhibited mitochondrial dysfunction and hypoxia, along with the elevated expression of necroptosis-related genes, consistent with that in both SLE B-cell microarray and real-time PCR verification. Expectedly, pretreatment with the receptor-interacting protein kinase 1 (RIPK1) inhibitor Necrostatin-1, and not the apoptosis inhibitor zVAD, suppressed B-cell death. Importantly, B cells from additional SLE patients also significantly displayed high expression levels of necroptosis-related genes compared with those from healthy donors. These data indicate that co-activation of TLR7 and BCR pathways can promote B cells to hyperactivation and ultimately necroptosis. Our finding provides a new explanation on B-cell lymphopenia in active SLE patients. These data suggest that extrinsic factors may increase the intrinsical abnormality of B cells in SLE patients.
doi:10.1038/cddis.2014.375
PMCID: PMC4225223  PMID: 25210799
6.  Magnetic Exchange Coupling and Anisotropy of 3d Transition Metal Nanowires on Graphyne 
Scientific Reports  2014;4:4014.
Applying two-dimensional monolayer materials in nanoelectronics and spintronics is hindered by a lack of ordered and separately distributed spin structures. We investigate the electronic and magnetic properties of one-dimensional zigzag and armchair 3d transition metal (TM) nanowires on graphyne (GY), using density functional theory plus Hubbard U (DFT + U). The 3d TM nanowires are formed on graphyne (GY) surfaces. TM atoms separately and regularly embed within GY, achieving long-range magnetic spin ordering. TM exchange coupling of the zigzag and armchair nanowires is mediated by sp-hybridized carbon, and results in long-range magnetic order and magnetic anisotropy. The magnetic coupling mechanism is explained by competition between through-bond and through-space interactions derived from superexchange. These results aid the realization of GY in spintronics.
doi:10.1038/srep04014
PMCID: PMC3918920  PMID: 24510164
7.  Enhanced tumor suppression in vitro and in vivo by co-expression of survivin-specific siRNA and wild-type p53 protein 
Shao, Y | Liu, Y | Shao, C | Hu, J | Li, X | Li, F | Zhang, L | Zhao, D | Sun, L | Zhao, X | Kopecko, DJ | Kalvakolanu, DV | Li, Y | Xu, DQ
Cancer gene therapy  2010;17(12):844-854.
The development of malignant prostate cancer involves multiple genetic alterations. For example, alterations in both survivin and p53 are reported to have crucial roles in prostate cancer progression. However, little is known regarding the interrelationships between p53 and survivin in prostate cancer. Our data demonstrate that the expression of survivin is inversely correlated with that of wtp53 protein (rs=0.548) in prostate cancer and in normal prostate tissues. We have developed a therapeutic strategy, in which two antitumor factors, small interfering RNA-survivin and p53 protein, are co-expressed from the same plasmid, and have examined their effects on the growth of PC3, an androgen-independent prostate cancer cell line. When p53 was expressed along with a survivin-specific short hairpin RNA (shRNA), tumor cell proliferation was significantly suppressed and apoptosis occurred. In addition, this combination also abrogated the expression of downstream target molecules such as cyclin-dependent kinase 4 and c-Myc, while enhancing the expression of GRIM19. These changes in gene expression occurred distinctly in the presence of survivin-shRNA/wtp53 compared with control or single treatment groups. Intratumoral injection of the co-expressed construct inhibited the growth and survival of tumor xenografts in a nude mouse model. These studies revealed evidence of an interaction between p53 and survivin proteins plus a complex signaling network operating downstream of the wtp53-survivin pathway that actively controls tumor cell proliferation, survival and apoptosis.
doi:10.1038/cgt.2010.41
PMCID: PMC3915357  PMID: 20706288
prostate cancer; p53; survivin; siRNA
8.  Understanding strong magnetostriction in Fe100−xGax alloys 
Scientific Reports  2013;3:3521.
Magnetostriction of ferromagnetic materials describes the change of their shape or dimension in response to the reorientation of magnetization under the influence of external magnetic field. Fe100−xGax binary alloys (Galfenol) have large magnetostriction and excellent ductility; and they are very promising rare-earth free materials for applications in sensors, actuators, energy-harvesters and spintronic devices. Here we report results of large-scale ab initio molecular dynamics (AIMD) simulations for Galfenol, especially regarding the mechanism that leads to the sudden drop of tetragonal magnetostriction at x ~ 19, a long-standing puzzle for the community. Based on rigid band analysis, we propose possible ways to further optimize the performance of Galfenol for device applications. For example, we found that the substitution of a small amount of Cu for Ga (1.6%) in certain configuration may double the magnetostriction of Galfenol.
doi:10.1038/srep03521
PMCID: PMC3865486  PMID: 24343479
9.  miR-874 regulates myocardial necrosis by targeting caspase-8 
Cell Death & Disease  2013;4(7):e709-.
Cardiomyocyte death is an important reason for the cardiac syndromes, such as heart failure (HF) and myocardial infarction (MI). In the heart diseases, necrosis is one of the main forms of cell death. MicroRNAs (miRNAs) are a class of small non-coding RNAs that mediate post-transcriptional gene silencing. Hitherto, it is not yet clear whether miRNA can regulate necrosis in cardiomyocyte. In this work, we performed a microarray to detect miRNAs in response to H2O2 treatment, and the results showed that miR-874 was substantially increased. We further studied the function of miR-874, and observed that knockdown of miR-874 attenuated necrosis in the cellular model and also MI in the animal model. We searched for the downstream mediator of miR-874 and identified that caspase-8 was a target of miR-874. Caspase-8 was able to antagonize necrosis. When suppressed by miR-874, caspase-8 lost the ability to repress necrotic program. In exploring the molecular mechanism by which miR-874 expression is regulated, we identified that Foxo3a could transcriptionally repress miR-874 expression. Foxo3a transgenic or knockout mice exhibited a low or high expression level of miR-874, and a reduced or enhanced necrosis and MI. Our present study reveals a novel myocardial necrotic regulating model, which is composed of Foxo3a, miR-874 and caspase-8. Modulation of their levels may provide a new approach for tackling myocardial necrosis.
doi:10.1038/cddis.2013.233
PMCID: PMC3730407  PMID: 23828572
myocardial necrosis; miR-874; caspase-8
10.  Aligned Silk-Based 3D Architectures for Contact Guidance in Tissue Engineering 
Acta Biomaterialia  2011;8(4):1530-1542.
An important challenge in the biomaterials field is to mimic the structure of functional tissues via cell and extracellular matrix (ECM) alignment and anisotropy. Toward this goal, silk-based scaffolds resembling bone lamellar structure were developed using a freeze-drying technique. The structure could be controlled directly by solute concentration and freezing parameters, resulting in lamellar scaffolds with regular morphology. Different post-treatments were investigated to induce water stability, such as methanol, water annealing and steam sterilization. The resulting structures exhibited significant differences in terms of morphological integrity, structure and mechanical properties. the lamellar thicknesses were around ~2,6 μm for the methanol treated scaffolds and ~5,8 μm for water-annealed. These values are in the range of the reported for human lamellar bone. Human bone marrow-derived mesenchymal stem cells (hMSCs) were seeded on these silk fibroin lamellar scaffolds and grown under osteogenic conditions to assess the effect of the microstructure on cell behaviour. Collagen in the newly deposited ECM, was found aligned along the lamellar architectures. In the case of methanol treated lamellar structures the hMSCs were able to migrate into the interior of the scaffolds producing a multilamellar hybrid construct. The present morphology constitutes a useful pattern onto which hMSCs cells attach and proliferate for guided formation of a highly oriented extracellular matrix.
doi:10.1016/j.actbio.2011.12.015
PMCID: PMC3289723  PMID: 22202909
Silk fibroin; scaffold; freeze-drying; directional freezing; tissue engineering; lamellar morphology; cell alignment
11.  A phase II study evaluating the safety and efficacy of an adenovirus-ΔLMP1-LMP2 transduced dendritic cell vaccine in patients with advanced metastatic nasopharyngeal carcinoma 
Annals of Oncology  2011;23(4):997-1005.
Background: Individuals with metastatic Epstein–Barr virus (EBV)-positive nasopharyngeal carcinoma (NPC) continue to have poor outcomes. To evaluate the ability of a dendritic cell (DC) vaccine to target subdominant EBV antigens LMP1 and LMP2 expressed by NPC cells, we vaccinated patients using autologous DCs transduced with an adenovirus encoding a truncated LMP1 (ΔLMP1) and full-length LMP2 (Ad-ΔLMP1-LMP2).
Materials and methods: Sixteen subjects with metastatic NPC received Ad-ΔLMP1-LMP2 DC vaccines i.d. biweekly for up to five doses. Toxicity, immune responses and clinical responses were determined.
Results: Most patients had extensive disease, with a median of three visceral sites of involvement (range 1–7). No significant toxicity was observed. Ad-ΔLMP1-LMP2 DCs induced delayed type hypersensitivity responses in 9 out of 12 patients, but although these DCs activated LMP1/2-specific T cells in vitro, no such increase in the frequency of peripheral LMP1/2-specific T cells was detected. Three patients had clinical responses including one with partial response (for 7½ months) and two with stable disease (for 6½ and 7½ months).
Conclusions: Ad-ΔLMP1-LMP2 transduced DCs can be successfully generated and safely administered to patients with advanced NPC. Since efficacy was limited, future studies should focus on DC vaccines with greater potency administered to subjects with less tumor burden.
doi:10.1093/annonc/mdr341
PMCID: PMC3314324  PMID: 21821548
dendritic cell vaccine; Epstein–Barr virus; nasopharyngeal carcinoma; recombinant adenovirus
12.  Adaptive Real-Time Closed-Loop Temperature Control for Ultrasound Hyperthermia Using Magnetic Resonance Thermometry 
Previous researchers have successfully demonstrated the application of temperature feedback control for thermal treatment of disease using MR thermometry. Using the temperature-dependent proton resonance frequency (PRF) shift, ultrasound heating for hyperthermia to a target organ (such as the prostate) can be tightly controlled. However, using fixed gain controllers, the response of the target to ultrasound heating varies with type, size, location, shape, stage of growth, and proximity to other vulnerable organs. To adjust for clinical variables, feedback self-tuning regulator (STR) and model reference adaptive control (MRAC) methods have been designed and implemented using real-time, online MR thermometry by adjusting the output power to an ultrasound array to quickly reach the hyperthermia target temperatures. The use of fast adaptive controllers in this application is advantageous because adaptive controllers do not require a priori knowledge of the initial tissue properties and blood perfusion and can quickly reach the steady-state target temperature in the presence of dynamic tissue properties (e.g., thermal conductivity, blood perfusion). This research was conducted to rapidly achieve and manage therapeutic temperatures from an ultrasound array using novel MRI-guided adaptive closed-loop controllers both in ex vivo and in vivo experiments. The ex vivo phantom experiments with bovine muscle (n = 5) show that within 6 ± 0.2 minutes, the tissue temperature increased by 8 ± 1.37°C. Using rabbits’ (n = 5) thigh muscle, the in vivo experiments demonstrated the target temperature reached 44.5°C ± 1.2°C in 8.0 ± 0.5 minutes. The preliminary in vivo experiment with canine prostate hyperthermia achieved 43 ± 2°C in 6.5 ± 0.5 minutes. These results demonstrate that the adaptive controllers with MR thermometry are able to effectively track the target temperature with dynamic tissue properties.
doi:10.1002/cmr.b.20046
PMCID: PMC3377976  PMID: 22723751
MR thermometry; adaptive temperature control; closed loop; ultrasound hyperthermia
14.  In Vivo Assessment of Chitosan/ β-Glycerophosphate as a New Liquid Embolic Agent 
Interventional Neuroradiology  2011;17(1):87-92.
Summary
We sought to assess the feasibility of using thermosensitive chitosan/β-glycerophosphate for embolotherapy. The renal arteries in nine rabbits were embolized with chitosan/β-glycerophosphate. The animals were studied angiographically and sacrificed at one week (n = 3), four weeks (n = 3), and eight weeks (n = 3) after embolotherapy. Histology was obtained at these three time points. Delivery of chitosan/β-glycerophosphate was successful in all cases. Complete occlusion was achieved in all cases. No recanalization was observed in the follow-up angiograms. No untoward inflammatory reactions were observed in the target renal arteries and infarcted kidneys during the histological examinations. Our preliminary feasibility evaluation in rabbit renal arteries indicates that C/GP is a satisfactory embolization agent.
PMCID: PMC3278031  PMID: 21561564
chitosan/β-glycerophosphate, liquid embolic agent, embolization, in vivo
15.  Nonlinear Elasto-Mammography for Characterization of Breast Tissue Properties 
Quantification of the mechanical behavior of normal and cancerous tissues has important implication in the diagnosis of breast tumor. The present work extends the authors' nonlinear elastography framework to incorporate the conventional X-ray mammography, where the projection of displacement information is acquired instead of full three-dimensional (3D) vector. The elastic parameters of normal and cancerous breast tissues are identified by minimizing the difference between the measurement and the corresponding computational prediction. An adjoint method is derived to calculate the gradient of the objective function. Simulations are conducted on a 3D breast phantom consisting of the fatty tissue, glandular tissue, and cancerous tumor, whose mechanical responses are hyperelastic in nature. The material parameters are identified with consideration of measurement error. The results demonstrate that the projective displacements acquired in X-ray mammography provide sufficient constitutive information of the tumor and prove the usability and robustness of the proposed method and algorithm.
doi:10.1155/2011/540820
PMCID: PMC3253468  PMID: 22235197
16.  Early childhood general anaesthesia exposure and neurocognitive development 
BJA: British Journal of Anaesthesia  2010;105(Suppl 1):i61-i68.
Summary
A great deal of concern has recently arisen regarding the safety of anaesthesia in infants and children. There is mounting and convincing preclinical evidence in rodents and non-human primates that anaesthetics in common clinical use are neurotoxic to the developing brain in vitro and cause long-term neurobehavioural abnormalities in vivo. An estimated 6 million children (including 1.5 million infants) undergo surgery and anaesthesia each year in the USA alone, so the clinical relevance of anaesthetic neurotoxicity is an urgent matter of public health. Clinical studies that have been conducted on the long-term neurodevelopmental effects of anaesthetic agents in infants and children are retrospective analyses of existing data. Two large-scale clinical studies are currently underway to further address this issue. The PANDA study is a large-scale, multisite, ambi-directional sibling-matched cohort study in the USA. The aim of this study is to examine the neurodevelopmental effects of exposure to general anaesthesia during inguinal hernia surgery before 36 months of age. Another large-scale study is the GAS study, which will compare the neurodevelopmental outcome between two anaesthetic techniques, general sevoflurane anaesthesia and regional anaesthesia, in infants undergoing inguinal hernia repair. These study results should contribute significant information related to anaesthetic neurotoxicity in children.
doi:10.1093/bja/aeq302
PMCID: PMC3000523  PMID: 21148656
anaesthesia, paediatric; children; neurocognitive outcome; neurotoxicity; risk
17.  Novel CaF2 Nanocomposite with High Strength and Fluoride Ion Release 
Journal of dental research  2010;89(7):739-745.
Secondary caries and restoration fracture remain common problems in dentistry. This study tested the hypothesis that combining nano-CaF2 and glass fillers would yield nanocomposites with high mechanical properties and F release. Novel CaF2 nanoparticles (56-nm) were synthesized via spray-drying and incorporated into resin. F release increased with increasing the nano-CaF2 content, or with decreasing pH (p < 0.05). F-release rates at 70–84 days were 1.13 µg/(cm2·day) and 0.50 µg/(cm2·day) for nanocomposites containing 30% and 20% nano-CaF2, respectively. They matched the 0.65 µg/(cm2·day) of resin-modified glass ionomer (p > 0.1). The nanocomposites had flexural strengths of 70–120 MPa, after 84-day immersion at pH 4, pH 5.5, and pH 7. These strengths were nearly three-fold that of resin-modified glass ionomer, and matched/exceeded a composite with little F release. In summary, novel CaF2 nanoparticles produced high F release at low filler levels, thereby making room in resin for reinforcement glass. This yielded nanocomposites with high F-release and stress-bearing properties, which may help reduce secondary caries and restoration fracture.
doi:10.1177/0022034510364490
PMCID: PMC3077944  PMID: 20439933
dental nanocomposite; CaF2 nanoparticles; fluoride release; stress-bearing; dental caries
18.  Novel CaF2 Nanocomposite with High Strength and Fluoride Ion Release 
Journal of Dental Research  2010;89(7):739-745.
Secondary caries and restoration fracture remain common problems in dentistry. This study tested the hypothesis that combining nano-CaF2 and glass fillers would yield nanocomposites with high mechanical properties and F release. Novel CaF2 nanoparticles (56-nm) were synthesized via spray-drying and incorporated into resin. F release increased with increasing the nano-CaF2 content, or with decreasing pH (p < 0.05). F-release rates at 70-84 days were 1.13 µg/(cm2·day) and 0.50 µg/(cm2·day) for nanocomposites containing 30% and 20% nano-CaF2, respectively. They matched the 0.65 µg/(cm2·day) of resin-modified glass ionomer (p > 0.1). The nanocomposites had flexural strengths of 70-120 MPa, after 84-day immersion at pH 4, pH 5.5, and pH 7. These strengths were nearly three-fold that of resin-modified glass ionomer, and matched/exceeded a composite with little F release. In summary, novel CaF2 nanoparticles produced high F release at low filler levels, thereby making room in resin for reinforcement glass. This yielded nanocomposites with high F-release and stress-bearing properties, which may help reduce secondary caries and restoration fracture.
doi:10.1177/0022034510364490
PMCID: PMC3077944  PMID: 20439933
dental nanocomposite; CaF2 nanoparticles; fluoride release; stress-bearing; dental caries
19.  Apical membrane rupture and backward bile flooding in acetaminophen-induced hepatocyte necrosis 
Cell Death & Disease  2011;2(7):e183-.
Morphological changes of hepatocyte death have so far only been described on cells in culture or in tissue sections. Using a high-resolution and high-magnification multiphoton microscopic system, we recorded in living mice serial changes of acetaminophen (APAP)-induced hepatocyte necrosis in relevance to metabolism of a fluorogenic bile solute. Initial changes of hepatocyte injury included basal membrane disruption and loss of mitochondrial membrane potential. An overwhelming event of rupture at adjacent apical membrane resulting in flooding of bile into these hepatocytes might ensue. Belbs formed on basal membrane and then dislodged into the sinusoid circulation. Transmission electron microscopy disclosed a necrotic hepatocyte depicting well the changes after apical membrane rupture and bile flooding. Administration of the antidote N-acetylcysteine dramatically reduced the occurrence of apical membrane rupture. The present results demonstrated a hidden but critical step of apical membrane rupture leading to irreversible APAP-induced hepatocyte injury.
doi:10.1038/cddis.2011.68
PMCID: PMC3199717  PMID: 21776021
acetaminophen; hepatocyte necrosis; multiphoton microscopy; intravital imaging
20.  Strong Nanocomposites with Ca, PO4, and F Release for Caries Inhibition 
Journal of dental research  2010;89(1):19-28.
This article reviews recent studies on: (1) the synthesis of novel calcium phosphate and calcium fluoride nanoparticles and their incorporation into dental resins to develop nanocomposites; (2) the effects of key microstructural parameters on Ca, PO4, and F ion release from nanocomposites, including the effects of nanofiller volume fraction, particle size, and silanization; and (3) mechanical properties of nanocomposites, including water-aging effects, flexural strength, fracture toughness, and three-body wear. This article demonstrates that a major advantage of using the new nanoparticles is that high levels of Ca, PO4, and F release can be achieved at low filler levels in the resin, because of the high surface areas of the nanoparticles. This leaves room in the resin for substantial reinforcement fillers. The combination of releasing nanofillers with stable and strong reinforcing fillers is promising to yield a nanocomposite with both stress-bearing and caries-inhibiting capabilities, a combination not yet available in current materials.
doi:10.1177/0022034509351969
PMCID: PMC3056546  PMID: 19948941
dental nanocomposite; nanoparticles; strength; Ca and PO4 ion release; fluoride release; tooth caries inhibition
21.  Initial stage of crystalline rubrene thin film growth on mica (0 0 1) 
Synthetic Metals  2011;161(3-4):271-274.
We have studied the morphology and the spatially resolved photoluminescence of rubrene thin films at the early stage of crystallization. The initial growth proceeds via the formation of a wetting layer and the nucleation of islands with an amorphous structure. Crystallization starts when the amorphous islands coalesce and needle like crystalline fibers are formed in the gap between islands. The crystalline fibers then grow on top and in between the original amorphous islands leading to an “open network” of islands. The latter acts as the basis for the growth of semi-crystalline spherulites.
doi:10.1016/j.synthmet.2010.11.033
PMCID: PMC3087472  PMID: 21552477
Organic thin films; Fluorescence spectroscopy; Fluorescence microscopy; Epitaxial growth; Rubrene
22.  Strong Nanocomposites with Ca, PO4, and F Release for Caries Inhibition 
Journal of Dental Research  2010;89(1):19-28.
This article reviews recent studies on: (1) the synthesis of novel calcium phosphate and calcium fluoride nanoparticles and their incorporation into dental resins to develop nanocomposites; (2) the effects of key microstructural parameters on Ca, PO4, and F ion release from nanocomposites, including the effects of nanofiller volume fraction, particle size, and silanization; and (3) mechanical properties of nanocomposites, including water-aging effects, flexural strength, fracture toughness, and three-body wear. This article demonstrates that a major advantage of using the new nanoparticles is that high levels of Ca, PO4, and F release can be achieved at low filler levels in the resin, because of the high surface areas of the nanoparticles. This leaves room in the resin for substantial reinforcement fillers. The combination of releasing nanofillers with stable and strong reinforcing fillers is promising to yield a nanocomposite with both stress-bearing and caries-inhibiting capabilities, a combination not yet available in current materials.
doi:10.1177/0022034509351969
PMCID: PMC3056546  PMID: 19948941
dental nanocomposite; nanoparticles; strength; Ca and PO4 ion release; fluoride release; tooth caries inhibition
23.  A selective COX‐2 inhibitor suppresses chronic pancreatitis in an animal model (WBN/Kob rats): significant reduction of macrophage infiltration and fibrosis 
Gut  2006;55(8):1165-1173.
Introduction
Therapeutic strategies to treat chronic pancreatitis (CP) are very limited. Other chronic inflammatory diseases can be successfully suppressed by selective cyclooxygenase 2 (COX‐2) inhibitors. As COX‐2 is elevated in CP, we attempted to inhibit COX‐2 activity in an animal model of CP (WBN/Kob rat). We then analysed the effect of COX‐2 inhibition on macrophages, important mediators of chronic inflammation.
Methods
Male WBN/Kob rats were continuously fed the COX‐2 inhibitor rofecoxib, starting at the age of seven weeks. Animals were sacrificed 2, 5, 9, 17, 29, 41, and 47 weeks later. In some animals, treatment was discontinued after 17 weeks, and animals were observed for another 24 weeks.
Results
Compared with the spontaneous development of inflammatory injury and fibrosis in WBN/Kob control rats, animals treated with rofecoxib exhibited a significant reduction and delay (p<0.0001) in inflammation. Collagen and transforming growth factor β synthesis were significantly reduced. Similarly, prostaglandin E2 levels were markedly lower, indicating strong inhibition of COX‐2 activity (p<0.003). If treatment was discontinued at 24 weeks of age, all parameters of inflammation strongly increased comparable with that in untreated rats. The correlation of initial infiltration with subsequent fibrosis led us to determine the effect of rofecoxib on macrophage migration. In chemotaxis experiments, macrophages became insensitive to the chemoattractant fMLP in the presence of rofecoxib.
Conclusion
In the WBN/Kob rat, chronic inflammatory changes and subsequent fibrosis can be inhibited by rofecoxib. Initial events include infiltration of macrophages. Cell culture experiments indicate that migration of macrophages is COX‐2 dependent.
doi:10.1136/gut.2005.077925
PMCID: PMC1856270  PMID: 16322109
chronic pancreatitis; macrophages; cyclooxygenases; infiltration; fibrosis
24.  Elastography Method for Reconstruction of Nonlinear Breast Tissue Properties 
Elastography is developed as a quantitative approach to imaging linear elastic properties of tissues to detect suspicious tumors. In this paper a nonlinear elastography method is introduced for reconstruction of complex breast tissue properties. The elastic parameters are estimated by optimally minimizing the difference between the computed forces and experimental measures. A nonlinear adjoint method is derived to calculate the gradient of the objective function, which significantly enhances the numerical efficiency and stability. Simulations are conducted on a three-dimensional heterogeneous breast phantom extracting from real imaging including fatty tissue, glandular tissue, and tumors. An exponential-form of nonlinear material model is applied. The effect of noise is taken into account. Results demonstrate that the proposed nonlinear method opens the door toward nonlinear elastography and provides guidelines for future development and clinical application in breast cancer study.
doi:10.1155/2009/406854
PMCID: PMC2709722  PMID: 19636362
25.  Bone mass and geometry of the tibia and the radius of master sprinters, middle and long distance runners, race-walkers and sedentary control participants: A pQCT study 
Bone  2009;45(1):91-97.
Mechanical loading is thought to be a determinant of bone mass and geometry. Both ground reaction forces and tibial strains increase with running speed. This study investigates the hypothesis that surrogates of bone strength in male and female master sprinters, middle and long distance runners and race-walkers vary according to discipline-specific mechanical loading from sedentary controls.
Bone scans were obtained by peripheral Quantitative Computed Tomography (pQCT) from the tibia and from the radius in 106 sprinters, 52 middle distance runners, 93 long distance runners and 49 race-walkers who were competing at master championships, and who were aged between 35 and 94 years. Seventy-five age-matched, sedentary people served as control group.
Most athletes of this study had started to practice their athletic discipline after the age of 20, but the current training regime had typically been maintained for more than a decade. As hypothesised, tibia diaphyseal bone mineral content (vBMC), cortical area and polar moment of resistance were largest in sprinters, followed in descending order by middle and long distance runners, race-walkers and controls. When compared to control people, the differences in these measures were always > 13% in male and > 23% in female sprinters (p < 0.001). Similarly, the periosteal circumference in the tibia shaft was larger in male and female sprinters by 4% and 8%, respectively, compared to controls (p < 0.001). Epiphyseal group differences were predominantly found for trabecular vBMC in both male and female sprinters, who had 15% and 18% larger values, respectively, than controls (p < 0.001). In contrast, a reverse pattern was found for cortical vBMD in the tibia, and only few group differences of lower magnitude were found between athletes and control people for the radius.
In conclusion, tibial bone strength indicators seemed to be related to exercise-specific peak forces, whilst cortical density was inversely related to running distance. These results may be explained in two, non-exclusive ways. Firstly, greater skeletal size may allow larger muscle forces and power to be exerted, and thus bias towards engagement in athletics. Secondly, musculoskeletal forces related to running can induce skeletal adaptation and thus enhance bone strength.
doi:10.1016/j.bone.2009.03.660
PMCID: PMC2832729  PMID: 19332164
Veteran athletes; Track and field runners; Race-walking; Bone strength; Volumetric bone mineral density; Exercise

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