IL-17 promotes osteoblast differentiation, bone regeneration, and remodeling in mice.

Bone homeostasis is maintained by concerted actions of bone-forming osteoblasts and bone-resorbing osteoclasts. A wide range of evidence indicates that a proinflammatory cytokine IL-17 promotes osteoclastogenesis. However, the role of IL-17 in osteoblasts is less well-understood. In the current study, the effect of IL-17 on osteogenic differentiation was investigated in mouse calvarial cells. IL-17 stimulated osteoblast differentiation, mineralization, proliferation, motility, and osteoblast-dependent osteoclastogenesis in vitro. The pro-osteogenic role of IL-17 was dependent on Act1 and the generation of reactive oxygen species. In a critical size calvarial defect model, IL-17 significantly augmented bone regeneration. Importantly, IL-17 also remarkably increased bone remodeling and restored osteoclastogenesis in zoledronate-treated mice. Furthermore, IL-17 conspicuously stimulated the formation of lamellar bones. These data not only provide a clue to understand the role of IL-17 in bone metabolism but also suggest possible applications in bone augmentation therapies.

Visualization of woven bone structure through analysis of biopsy specimens using synchrotron radiation and conventional X-ray microcomputed tomography.

This study explores the application of synchrotron radiation and conventional microcomputed tomography (SR-µCT and C-µCT, respectively) in evaluating bone-biopsy specimens. Bone-biopsy specimens were obtained using a trephine bur during bone-graft removal for implant placement six months after performing a maxillary sinus bone-graft procedure. Image data of specimens were obtained using SR-µCT and C-µCT. SR-µCT was performed using the 6C biomedical imaging beamline at the Pohang Accelerator Laboratory with a monochromatic X-ray beam of 23 keV, and C-µCT was performed using a table-top CT scanner (Skyscan 1272). Reconstruction images obtained using the two methods were qualitatively compared with 2D images evaluated under 3D visualization. The SR-µCT images, especially of the new-bone-graft-woven-bone formation, were less noisy and sharper than the C-µCT images. To evaluate the new-bone-graft-woven-bone formation, only the SR-µCT images showed areas of new bone (NB) formation with bone substitute (BS; Bio-Oss) and woven bone (WB) contact, and correctly visualized true 3D structures of bone formation. Hence, µCT techniques are non-destructive and can provide detailed images of bone biopsy. In particular, SR-µCT can be used to obtain improved image quality with contrast of NB, BS and WB, demonstrating a level of detail comparable with bone formation. SR-µCT could be an unbiased 3D alternative for imaging WB formation and for high-throughput analysis.

High-Throughput Analysis of New Bone Formation and Bone Substitutes After Maxillary Sinus Floor Elevation Using Synchrotron Radiation Micro-Computed Tomography.

This study addresses the usability of synchrotron radiation micro-computed tomography (SR-µCT) for the high-throughput examination of bone biopsy specimens harvested from maxillary sinus floor elevation (MSFE) patients. The experimental procedure devised for efficient data acquisition and volume analysis of bone biopsy specimens of sinus lift using SR-µCT is presented. The measuring was done in approximately one minute per field of view; 3D image visualization and volume analysis could be performed in one hour. Six months after the sinus floor augmentation procedure, bone biopsy specimens were collected. Six specimens were studied. The percentages of bone measured by 3D volumetric analysis using SR-µCT and 2D area analysis using conventional histomorphometry were compared. A specimen was measured in any cross section, and the analysis was readily extended to the entire volume of the specimen. Significant differences between the 2D and the 3D measurement results were revealed. Based on our observations, we report structural inhomogeneity in the grafted volume of the MSFE site. The new bone volume assessed by SR-µCT correlates with the percentage of bone as assessed by conventional 2D histologic photomicrographs. SR-µCT is thus a reliable technique to determine the volume of newly formed bone at the MSFE.

Effects of Enhanced Hydrophilic Titanium Dioxide-Coated Hydroxyapatite on Bone Regeneration in Rabbit Calvarial Defects.

The regeneration of bone defects caused by periodontal disease or trauma is an important goal. Porous hydroxyapatite (HA) is an osteoconductive graft material. However, the hydrophobic properties of HA can be a disadvantage in the initial healing process. HA can be coated with TiO2 to improve its hydrophilicity, and ultraviolet irradiation (UV) can further increase the hydrophilicity by photofunctionalization. This study was designed to evaluate the effect of 5% TiO2-coated HA on rabbit calvarial defects and compare it with that of photofunctionalization on new bone in the early stage. The following four study groups were established, negative control, HA, TiO2-coated HA, and TiO2-coated HA with UV. The animals were sacrificed and the defects were assessed by radiography as well as histologic and histomorphometric analyses. At 2 and 8 weeks postoperatively, the TiO2-coated HA with UV group and TiO2-coated HA group showed significantly higher percentages of new bone than the control group (p < 0.05). UV irradiation increased the extent of new bone formation, and there was a significant difference between the TiO2-coated HA group and TiO2-coated HA with UV group. The combination of TiO2/HA and UV irradiation in bone regeneration appears to induce a favorable response.

Enhanced production of reactive oxygen species by gadolinium oxide nanoparticles under core-inner-shell excitation by proton or monochromatic X-ray irradiation: implication of the contribution from the interatomic de-excitation-mediated nanoradiator effect to dose enhancement.

Core-inner-valence ionization of high-Z nanoparticle atomic clusters can de-excite electrons through various interatomic de-excitation processes, thereby leading to the ionization of both directly exposed atoms and adjacent neutral atoms within the nanoparticles, and to an enhancement in photon-electron emission, which is termed the nanoradiator effect. To investigate the nanoradiator-mediated dose enhancement in the radio-sensitizing of high-Z nanoparticles, the production of reactive oxygen species (ROS) was measured in a gadolinium oxide nanoparticle (Gd-oxide NP) solution under core-inner-valence excitation of Gd with either 50 keV monochromatic synchrotron X-rays or 45 MeV protons. This measurement was compared with either a radiation-only control or a gadolinium-chelate magnetic resonance imaging contrast agent solution containing equal amounts of gadolinium as the separate atomic species in which Gd-Gd interatomic de-excitations are absent. Ionization excitations followed by ROS measurements were performed on nanoparticle-loaded cells or aqueous solutions. Both photoexcitation and proton impact produced a dose-dependent enhancement in the production of ROS by a range of factors from 1.6 to 1.94 compared with the radiation-only control. Enhanced production of ROS, by a factor of 1.83, was observed from Gd-oxide NP atomic clusters compared with the Gd-chelate molecule, with a Gd concentration of 48 µg/mL in the core-level photon excitation, or by a factor of 1.82 under a Gd concentration of 12 µg/mL for the proton impact at 10 Gy (p < 0.02). The enhanced production of ROS in the irradiated nanoparticles suggests the potential for additional therapeutic dose enhancements in radiation treatment via the potent Gd-Gd interatomic de-excitation-driven nanoradiator effect.

Synchrotron Radiation Refraction-Contrast Computed Tomography Based on X-ray Dark-Field Imaging Optics of Pulmonary Malignancy: Comparison with Pathologic Examination.

Refraction-contrast computed tomography based on X-ray dark-field imaging (XDFI) using synchrotron radiation (SR) has shown superior resolution compared to conventional absorption-based methods and is often comparable to pathologic examination under light microscopy. This study aimed to investigate the potential of the XDFI technique for clinical application in lung cancer diagnosis. Two types of lung specimens, primary and secondary malignancies, were investigated using an XDFI optic system at beamline BL14B of the High-Energy Accelerator Research Organization Photon Factory, Tsukuba, Japan. Three-dimensional reconstruction and segmentation were performed on each specimen. Refraction-contrast computed tomographic images were compared with those obtained from pathological examinations. Pulmonary microstructures including arterioles, venules, bronchioles, alveolar sacs, and interalveolar septa were identified in SR images. Malignant lesions could be distinguished from the borders of normal structures. The lepidic pattern was defined as the invasive component of the same primary lung adenocarcinoma. The SR images of secondary lung adenocarcinomas of colorectal origin were distinct from those of primary lung adenocarcinomas. Refraction-contrast images based on XDFI optics of lung tissues correlated well with those of pathological examinations under light microscopy. This imaging method may have the potential for use in lung cancer diagnosis without tissue damage. Considerable equipment modifications are crucial before implementing them from the lab to the hospital in the near future.

Effects of gold nanoparticles on normal hepatocytes in radiation therapy.

Background: Gold nanoparticles (GNP, AuNPs) have received much attention as a tool to improve the therapeutic index of radiation therapy. This study aimed to evaluate the normal in vitro toxicity of AuNPs at kilovoltage energies on hepatocytes to provide scientific support for using AuNPs with radiotherapy. Methods: Using the same treatment protocol applied to tumor cell lines, hepatocytes were exposed to AuNPs and/or radiation at various time points. Results: The combination of X-ray irradiation and AuNPs did not have any significant effect on cell survival and apoptosis in normal hepatocytes. Furthermore, the combination treatment resulted in no or little change in the level of gamma-H2A histone family member X (γ-H2AX), a marker for DNA double-strand breaks (DSB), nor on the proportion of cells in the G2/M phase. Additionally, interleukin-8 (IL-8) secretion was measured using an enzyme-linked immunosorbent assay (ELISA) to assess its role in tumor progression and angiogenesis. The combination of irradiation and AuNP treatment revealed no significant reduction in hepatocyte viability, proliferation, or secretory capacity compared to cells receiving either treatment alone. According to this study, AuNPs in combination with radiation do have potentially in the treatment of hepatocellular carcinoma (HCC) with no critical cytotoxicity on normal tissue. Conclusions: Therefore, it is postulated that radiation and AuNPs are an effective combination therapy against HCC with no little cytotoxic effects on normal tissue, a hypothesis which warrants further investigation in in vivo, as well as in in vitro.

Proton Stimulation Targeting Plaque Magnetite Reduces Amyloid-ß Plaque and Iron Redox Toxicity and Improves Memory in an Alzheimer's Disease Mouse Model.

BACKGROUND: The coexistence of magnetite within protein aggregates in the brain is a typical pathologic feature of Alzheimer's disease (AD), and the formation of amyloid-ß (Aß) plaques induces critical impairment of cognitive function. OBJECTIVE: This study aimed to investigate the therapeutic effect of proton stimulation (PS) targeting plaque magnetite in the transgenic AD mouse brain. METHODS: A proton transmission beam was applied to the whole mouse brain at a single entrance dose of 2 or 4 Gy to test the effect of disruption of magnetite-containing Aß plaques by electron emission from magnetite. The reduction in Aß plaque burden and the cognitive function of the PS-treated mouse group were assayed by histochemical analysis and memory tests, respectively. Aß-magnetite and Aß fibrils were treated with PS to investigate the breakdown of the amyloid protein matrix. RESULTS: Single PS induced a 48-87%reduction in both the amyloid plaque burden and ferrous-containing magnetite level in the early-onset AD mouse brain while saving normal tissue. The overall Aß plaque burden (68-82%) and (94-97%) hippocampal magnetite levels were reduced in late onset AD mice that showed improvements in cognitive function after PS compared with untreated AD mice (p < 0.001). Analysis of amyloid fibrils after exposure to a single 2 or 4 Gy proton transmission beam demonstrated that the protein matrix was broken down only in magnetite-associated Aß fibrils. CONCLUSION: Single PS targeting plaque magnetite effectively decreases the amyloid plaque burden and the ferrous-containing magnetite level, and this effect is useful for memory recovery.

Tumor-treating fields as a proton beam-sensitizer for glioblastoma therapy.

Few advances in GBM treatment have been made since the initiation of the Stupp trials in 2005. Experimental studies on immunotherapy drugs, molecular inhibitors, radiation dosage escalation and vascular growth factor blockers have all failed to provide satisfactory outcomes. TTFields therapy, on the other hand, have emerged as a viable substitute to therapies like radiation in GBM patients having a highly immunosuppressive tumor microenvironment. To enhance the biofunctional impacts, we explored the combination events with TTFields and proton treatment in this study. We conducted a cell viability test, a cell death detection evaluation, a ROS analysis, a three-dimensional (3D) culture system, and a migration assay. The combination of proton radiation and TTFields therapy laid a substantial anticancer impact on the F98 and U373 as compared to the consequences of either of these therapies used separately. The combination proton beam therapy used by TTFields was very successful in curbing GBM from migrating. GBM cell metastasis is restricted by TTFields combined proton by downregulating the MAPK, NF-κB, and PI3K/AKT indicating pathways, caused by reduced EMT marker expression. These findings furnish biological proof for the molecular grounds of TTFields in combination with proton used for GBM therapy.

Therapeutic application of metallic nanoparticles combined with particle-induced x-ray emission effect.

Metallic nanoparticles (MNP) are able to release localized x-rays when activated with a high energy proton beam by the particle-induced x-ray emission (PIXE) effect. The exploitation of this phenomenon in the therapeutic irradiation of tumors has been investigated. PIXE-based x-ray emission directed at CT26 tumor cells in vitro, when administered with either gold (average diameter 2 and 13 nm) or iron (average diameter 14 nm) nanoparticles (GNP or SNP), increased with MNP solution concentration over the range of 0.1-2 mg ml(-1). With irradiation by a 45 MeV proton therapy (PT) beam, higher concentrations had a decreased cell survival fraction. An in vivo study in CT26 mouse tumor models with tumor regression assay demonstrated significant tumor dose enhancement, thought to be a result of the PIXE effect when compared to conventional PT without MNP (radiation-only group) using a 45 MeV proton beam (p < 0.02). Those receiving GNP or SNP injection doses of 300 mg kg(-1) body weight before proton beam therapy demonstrated 90% or 75% tumor volume reduction (TVR) in 20 days post-PT while the radiation-only group showed only 18% TVR and re-growth of tumor volume after 20 days. Higher complete tumor regression (CTR) was observed in 14-24 days after a single treatment of PT with an average rate of 33-65% for those receiving MNP compared with 25% for the radiation-only group. A lower bound of therapeutic effective MNP concentration range, in vivo, was estimated as 30-79 µg g(-1) tissue for both gold and iron nanoparticles. The tumor dose enhancement may compensate for an increase in entrance dose associated with conventional PT when treating large, solid tumors with a spread-out Bragg peak (SOBP) technique. The use of a combined high energy Bragg peak PT with PIXE generated by MNP, or PIXE alone, may result in new treatment options for infiltrative metastatic tumors and other diffuse inflammatory diseases.

Improved bone regeneration using collagen-coated biphasic calcium phosphate with high porosity in a rabbit calvarial model.

Many growth factors have been paired with synthetic bone grafts to accelerate the healing process in vivo. Collagen has been particularly examined as a mediator of the enhancement of bone regeneration. This study investigated the new bone formation potential of micro-macroporous biphasic calcium phosphate (m-BCP), high porosity biphasic calcium phosphate (p-BCP), and collagen-coated p-BCP (cp-BCP) using a rabbit calvarial defect model. At 2 or 8 weeks after surgery, bone tissue was collected. The three-dimensional analysis of new bone formation using synchrotron radiation micro-computed tomography and histological study were conducted. The new bone formation values observed at 2 and 8 weeks in the negative control, m-BCP, p-BCP, and cp-BCP groups were 11.21 ± 1.36 mm3, 21.75 ± 1.18 mm3, 24.59 ± 1.26 mm3, and 29.54 ± 2.72 mm3, respectively, and 18.34 ± 3.99 mm3, 32.27 ± 3.78 mm3, 43.12 ± 1.61 mm3, and 58.20 ± 3.84 mm3, respectively. New bone formation was greatest in the cp-BCP group, while the amount of new bone at 8 weeks was higher than at 2 weeks in each group. The use of cp-BCP to enhance new bone formation during the healing period could improve bone regeneration.

In-situ analysis of the hydration ability of bone graft material using a synchrotron radiation X-ray micro-CT.

The conventional micro-computed tomography (µCT) is a non-destructive imaging technique used for obtaining 2D and 3D information for scaffolds. The main composition and internal structure are important in mimicking and designing the characteristics of natural bone. This study was three-dimensional evaluating the external or internal structures and the hydration effects of bone graft materials by using the in-situ image technique. Synchrotron radiation micro-computed tomography (SR-µCT) was used to extract information on the geometry of two biphasic calcium phosphates (BCP) with identical chemicals and different micro-macro porosity, pore size distribution, and pore interconnection pathways. Volume analysis by hydration was used to measure the two bone graft materials at 0, 5, and 10-min intervals. The SR-µCT image was achieved with information regarding the internal pore structure and hydration effects evaluated under 3D visualization. Both types of bone graft materials showed structures suitable for tissue engineering applications. The SR-µCT in-situ techniques with 3D information provided a detailed view of the structures. Thus, SR-µCT could be an available, unbiased 3D alternative to in-situ analysis.

Effects of an electric toothbrush combined with 3-color light-emitting diodes on antiplaque and bleeding control: a randomized controlled study.

PURPOSE: This randomized controlled study aimed to evaluate the effects of an electric toothbrush with 3 colors of light-emitting diodes (LEDs) on antiplaque and bleeding control. METHODS: This randomized, placebo-controlled, double-blinded, parallel-group clinical trial included 50 healthy adults with gingivitis, who were randomly assigned to 2 groups. The experimental group used electric toothbrushes with 3 colors of LEDs and the control group used the same electric toothbrush as the experimental group, but with LED sources with one-hundredth of the strength. The subjects used the electric toothbrush 3 times a day for 4 minutes each time. As clinical indices, bleeding on marginal probing (BOMP), the Löe-Silness gingival index (GI), and the Turesky-Quigley-Hein plaque index (QHI) were assessed at baseline, at 3 weeks, and at 6 weeks. RESULTS: There were significant decreases in all clinical indices (BOMP, GI, QHI) in both the experimental and control groups compared to baseline at 3 weeks and at 6 weeks. In a comparison between the experimental and control groups, no statistically significant differences were observed for any clinical indices at 3 weeks (P>0.05). However, at 6 weeks, statistically significant differences were observed between the experimental and control groups in BOMP and GI, which are indicators of gingival inflammation (P<0.05). CONCLUSIONS: This study demonstrated that an electric toothbrush combined with 3-color LEDs reduced gingival bleeding and inflammation after 6 weeks.

Molecular mechanisms underlying the enhancement of carbon ion beam radiosensitivity of osteosarcoma cells by miR-29b.

Carbon ion radiotherapy (CIRT) is more effective than conventional photon beam radiotherapy in treating osteosarcoma (OSA); however, the outcomes of CIRT alone are still unsatisfactory. In this study, we aimed to investigate whether miR-29b acts as a radiosensitizer for CIRT. The OSA cell lines U2OS and KHOS were treated with carbon ion beam alone, γ-ray irradiation alone, or in combination with an miR-29b mimic. OSA cell death as well as invasive and migratory abilities were analyzed through viability, colony formation, Transwell, and apoptosis assays. miR-29 expression was downregulated in OSA tissues compared to that in normal tissues and was associated with metastasis and relapse in patients with OSA. Further, miR-29b was found to directly target the transcription factor Sp1 and suppress the activation of the phosphatase and tensin homolog (PTEN)-AKT pathway. Conversely, Sp1 was found to attenuate the inhibitory effects of miR-29b in OSA cells. When used in combination with miR-29b mimic, carbon ion beam markedly inhibited invasion, migration, and proliferation of OSA cells and promoted apoptosis by inhibiting AKT phosphorylation in a Sp1/PTEN-mediated manner. Taken together, miR-29b mimic improved the radiosensitivity of OSA cells via the PTEN-AKT-Sp1 signaling pathway, presenting a novel strategy for the development of carbon ion beam combination therapy.

Anti-Flt1 peptide and cyanine-conjugated gold nanoparticles for the concurrent antiangiogenic and endothelial cell proton treatment.

Anti-Flt1 peptide of GNQWFI binds to vascular endothelial growth factor receptor 1 (VEGFR1 or Flt1) and prevents binding of VEGF, inhibiting VEGFR1-mediated endothelial cell migration and tube formation. Bare gold nanoparticle (AuNP) was known to have anti-angiogenic properties by specific binding with VEGF. In this study, anti-Flt1 peptide (GGNQWFI) and cyanine were chemically conjugated to AuNPs (Flt1@AuNP-cyanine 5.5 or Flt1@AuNP-hydrocyanine 5.5 [HCy5.5]) to enhance antiangiogenic properties with targeting to VEGFR-1 as well as producing Coulomb nanoradiator therapeutic effect on the retinal endothelial cells. Anti-Flt1 AuNP complex showed binding with VEGFR-1 and showed more protein-induced fluorescence enhancement (PIFE) by various VEGFs compared with bare AuNPs, suggesting enhanced antiangiogenic properties compared to bare AuNP. Nonfluorescent Flt1@AuNP-HCy5.5 successfully reacted with reactive oxygen species (ROS) produced from Fenton reactions or a proton-induced Coulomb nanoradiator, enabling quenching-free oxidant fluorescence ROS imaging in HRMECs under oxidative stress. Flt1@AuNP-HCy5.5 alone induced 50% greater cytotoxicity for HRMECs compared to bare AuNPs and 80% greater cell death by the Au-nanoradiator effect. In conclusion, this study describes a new therapeutic anti-Flt1 gold nanocomplex with enhanced antiangiogenic properties and nanoradiator-mediated cytotoxicity on retinal endothelial cells. © 2018 Wiley Periodicals, Inc. J Biomed Mater Res Part B: Appl Biomater 107B: 1272-1283, 2019.

Photofunctionalizing effects of hydroxyapatite combined with TiO2 on bone regeneration in rabbit calvarial defects.

The hydrophilicity of bone graft material generally used as a carrier can play an important role in regulating bone morphogenetic protein (BMP) expression at the bone graft site. The hydrophilicity, altering physicochemical properties, and enhancing biological capabilities, can be increased via surface modification through ultraviolet (UV) photofunctionalization and the effect on de novo osteogenesis could be further improved. Therefore, this study aimed to assess the effects of UV-irradiated TiO2 -coated hydroxyapatite (HA) in combination with rhBMP-2 on bone regeneration in rabbit calvarial defects. The hydrophilicity of HA and TiO2 -coated HA pellets was evaluated by measuring the contact angle of water droplets with UV irradiation. To compare de novo osteogenesis in rabbit calvarial defects, the rabbits were segregated into four different groups: negative control, HA, TiO2 -coated HA, and TiO2 -coated HA with UV; histomorphometric analysis and micro-computed tomography (µCT) imaging were performed after 4 and 8 weeks. In vivo analysis revealed that de novo osteogenesis occurred on the critical size defects in all groups and was significantly increased in the TiO2 -coated HA with UV group than in other groups (p < 0.05). The present results indicate that UV photofunctionalization promotes de novo osteogenesis. © 2018 Wiley Periodicals, Inc. J Biomed Mater Res Part B: Appl Biomater 107B: 1953-1959, 2019.

Intravitreal implantable magnetic micropump for on-demand VEGFR-targeted drug delivery.

In this paper, we propose an intravitreal implantable magnetic micropump integrated with micro check valve capable of on-demand vascular endothelial growth factor receptor (VEGFR)-targeted drug delivery for the treatment of age-related macular degeneration, diabetic retinopathy and other eye pathologies characterized by ocular neoangiogenesis. Precise on-demand drug release is realized by the deflection of the magnetic membrane assembly according to the external magnetic field, and the membrane assembly consists of a thin elastic polydimethylsiloxane (PDMS) membrane and a cylindrical magnetic nanoparticle-PDMS composite block. Additionally, a micro check valve composed of two PDMS layers was integrated into the micropump to realize a diode-like one-directional drug delivery and prevent undesired drug diffusion. For specifically targeting VEGFR and suppression of VEGF-induced proliferation of microvascular endothelial cells, anti-Flt1 gold nanocomplexes are synthesized. In vitro and in vivo experiments and quantitative analysis are carried out in order to verify our proposed concept: precise drug release control according to the external magnetic field, targeting to microvascular endothelial cells, and efficient and on-demand drug delivery from the proposed micropump to the macular area of rabbit's eye.

Reactive oxygen species-based measurement of the dependence of the Coulomb nanoradiator effect on proton energy and atomic Z value.

PURPOSE: The Coulomb nanoradiator (CNR) effect produces the dose enhancement effects from high-Z nanoparticles under irradiation with a high-energy ion beam. To gain insight into the radiation dose and biological significance of the CNR effect, the enhancement of reactive oxygen species (ROS) production from iron oxide or gold NPs (IONs or AuNPs, respectively) in water was investigated using traversing proton beams. METHODS AND MATERIALS: The dependence of nanoradiator-enhanced ROS production on the atomic Z value and proton energy was investigated. Two biologically important ROS species were measured using fluorescent probes specific to •OH or [Formula: see text] in a series of water phantoms containing either AuNPs or IONs under irradiation with a 45- or 100-MeV proton beam. RESULTS: The enhanced generation of hydroxyl radicals (•OH) and superoxide anions ([Formula: see text]) was determined to be caused by the dependence on the NP concentration and proton energy. The proton-induced Au or iron oxide nanoradiators exhibited different ROS enhancement rates depending on the proton energy, suggesting that the CNR radiation varied. The curve of the superoxide anion production from the Au-nanoradiator showed strong non-linearity, unlike the linear behavior observed for hydroxyl radical production and the X-ray photoelectric nanoradiator. In addition, the 45-MeV proton-induced Au nanoradiator exhibited an ROS enhancement ratio of 8.54/1.50 ([Formula: see text] / •OH), similar to that of the 100-KeV X-ray photoelectric Au nanoradiator (7.68/1.46). CONCLUSIONS: The ROS-based detection of the CNR effect revealed its dependence on the proton beam energy, dose and atomic Z value and provided insight into the low-linear energy transfer (LET) CNR radiation, suggesting that these factors may influence the therapeutic efficacy via chemical reactivities, transport behaviors, and intracellular oxidative stress.

Effects of Escherichia Coli-derived Recombinant Human Bone Morphogenetic Protein-2 Loaded Porous Hydroxyaptite-based Ceramics on Calvarial Defect in Rabbits.

BACKGROUND: Recombinant human bone morphogenetic proteins (rhBMPs) have been widely used in regenerative therapies to promote bone formation. The production of rhBMPs using bacterial systems such as Escherichia coli (E. coli) is estimated to facilitate clinical applications by lowering the cost without compromising biological activity. In clinical practice, rhBMP-2 and osteoconductive carriers (e.g., hydroxyapatite [HA] and bovine bone xenograft) are used together. This study examined the effect of E. coli-derived rhBMP-2 combined with porous HA-based ceramics on calvarial defect in rabbits. METHODS: Six adult male New Zealand white rabbits were used in this study. The experimental groups were divided into the following 4 groups: untreated (NC), bovine bone graft (BO), porous HA (HA) and porous HA with rhBMP-2 (HA-BMP). Four transosseous defects of 8 mm in diameter were prepared using stainless steel trephine bur in the frontal and parietal bones. Histological and histomorphometric analyses at 4 weeks after surgery revealed significant new bone formation by porous HA alone. RESULTS: HA-BMP showed significantly higher degree of bone formation compared with BO and HA group (P<0.05). The average new bone formation % (new bone area per total defect area) of NC, BO, HA, and HA-BMP at 4-week after surgery were 12.65±5.89%, 29.63±6.99%, 28.86±6.17% and 49.56±8.23%, respectively. However, there was no statistical difference in the bone formation between HA and BO groups. CONCLUSIONS: HA-BMP promoted more bone formation than NC, BO and HA alone. Thus, using E. coli-derived rhBMP-2 combined with porous HA-based ceramics can promote new bone formation.

Synchrotron tomographic images from human lung adenocarcinoma: Three-dimensional reconstruction and histologic correlations.

High-resolution tomographic images using synchrotron X-rays are expected to provide detailed reflection of microstructures, thereby allowing for the examination of histologic structures without destruction of the specimen. This study aims to evaluate the synchrotron tomographic images of mixed ground-glass opacity excised on 5-mm sections in comparison to pathologic examination. The Institutional Review Board of our institute approved this retrospective study, and written informed consent was obtained from each patient whose lung tissue would be used. Obtained lung cancer specimens were brought to the multiple Wiggler 6C beam line at the Pohang Light Source (PLS-II) in Korea, and phase contrast X-ray images were obtained in November 2016. The X-ray emanated from a bending magnet of the electron storage ring with electron energy of 3 GeV, and a typical beam current was 320 mA. Reconstructed tomographic images were compared with images from histologic slides obtained from the same samples. Pulmonary microstructures including terminal bronchioles, alveolar sacs, and vasculature were identified with phase contrast X-ray images. Images from normal lung tissue and mixed ground-glass opacity were clearly distinguishable. Hyperplasia of the interalveolar septum and dysplasia of microstructure were clearly identified. The imaging findings correlated well with hematoxylin-eosin stained specimens. Tomographic images using synchrotron radiation have the potential for clinical applications. With refinement, this technique may become a diagnostic tool for detection of lung cancer.