Migration of cells along the right direction is of paramount importance in a number of in vivo circumstances such as immune response, embryonic developments, morphogenesis, and healing of wounds and scars. While it has been known for a while that spatial gradients in chemical cues guide the direction of cell migration, the significance of the gradient in mechanical cues, such as stiffness of extracellular matrices (ECMs), in directed migration of cells has only recently emerged. With advances in synthetic chemistry, micro-fabrication techniques, and methods to characterize mechanical properties at a length scale even smaller than a single cell, synthetic ECMs with spatially controlled stiffness have been created with variations in design parameters. Since then, the synthetic ECMs have served as platforms to study the migratory behaviors of cells in the presence of the stiffness gradient of ECM and also as scaffolds for the regeneration of tissues. In this review, we highlight recent studies in cell migration directed by the stiffness gradient, called durotaxis, and discuss the mechanisms of durotaxis. We also summarize general methods and design principles to create synthetic ECMs with the stiffness gradients and, finally, conclude by discussing current limitations and future directions of synthetic ECMs for the study of durotaxis and the scaffold for tissue engineering.
Artificial Cells ; Cell Movement ; Chemistry ; Cicatrix ; Cues ; Embryonic Development ; Extracellular Matrix ; Female ; Hydrogel* ; Hydrogels* ; Morphogenesis ; Pregnancy ; Regeneration ; Tissue Engineering* ; Wounds and Injuries

Central serous chorioretinopathy may induce poor eyesight and serous retinal detachment. However, its exact cause has not been well established thus far. It can be associated with systemic high-dose corticosteroid treatment mainly for young and middle-aged men and may spontaneously regress or recur after withdrawal from corticosteroid. After corticosteroid administration for Behcet's disease, it is necessary to identify any ocular symptoms. Behcet's disease can lead to the development of ocular complications, such as uveitis, hypopyon, retinal vasculitis, optic neuritis, angiogenesis, secondary cataract, and glaucoma. It is possible to diagnose any of these complications via optical coherence tomography and digital indocyanine green angiography. It is easy to neglect an ocular symptom that may appear after a low-dose corticosteroid treatment as an ocular complication in patients with Behcet's disease. Thus, we report on a case concerning high-dose corticosteroid treatment with a literature review.
Angiography ; Behcet Syndrome ; Capsule Opacification ; Central Serous Chorioretinopathy* ; Glaucoma ; Humans ; Indocyanine Green ; Male ; Optic Neuritis ; Retinal Detachment ; Retinal Vasculitis ; Tomography, Optical Coherence ; Uveitis

Central serous chorioretinopathy may induce poor eyesight and serous retinal detachment. However, its exact cause has not been well established thus far. It can be associated with systemic high-dose corticosteroid treatment mainly for young and middle-aged men and may spontaneously regress or recur after withdrawal from corticosteroid. After corticosteroid administration for Behcet's disease, it is necessary to identify any ocular symptoms. Behcet's disease can lead to the development of ocular complications, such as uveitis, hypopyon, retinal vasculitis, optic neuritis, angiogenesis, secondary cataract, and glaucoma. It is possible to diagnose any of these complications via optical coherence tomography and digital indocyanine green angiography. It is easy to neglect an ocular symptom that may appear after a low-dose corticosteroid treatment as an ocular complication in patients with Behcet's disease. Thus, we report on a case concerning high-dose corticosteroid treatment with a literature review.
Angiography ; Behcet Syndrome ; Capsule Opacification ; Central Serous Chorioretinopathy ; Glaucoma ; Humans ; Indocyanine Green ; Male ; Optic Neuritis ; Retinal Detachment ; Retinal Vasculitis ; Tomography, Optical Coherence ; Uveitis

We studied a Monte Carlo simulation of the proton beam delivery system at the National Cancer Center (NCC) using the Geant4 Monte Carlo toolkit and tested its feasibility as a dose verification framework. The Monte Carlo technique for dose calculation methodology has been recognized as the most accurate way for understanding the dose distribution in given materials. In order to take advantage of this methodology for application to externalbeam radiotherapy, a precise modeling of the nozzle elements along with the beam delivery path and correct initial beam characteristics are mandatory. Among three different treatment modes, double/single.scattering, uniform scanning and pencil beam scanning, we have modeled and simulated the double.scattering mode for the nozzle elements, including all components and varying the time and space with the Geant4.8.2 Monte Carlo code. We have obtained simulation data that showed an excellent correlation to the measured dose distributions at a specific treatment depth. We successfully set up the Monte Carlo simulation platform for the NCC proton therapy facility. It can be adapted to the precise dosimetry for therapeutic proton beam use at the NCC. Additional Monte Carlo work for the full proton beam energy range can be performed.
Proton Therapy ; Protons* ; Radiotherapy

Background: Excessive proliferation and migration of vascular smooth muscle cells (VSMCs), which contributes to the development of occlusive vascular diseases, requires elevated mitochondrial oxidative phosphorylation to meet the increased requirements for energy and anabolic precursors. Therefore, therapeutic strategies based on blockade of mitochondrial oxidative phosphorylation are considered promising for treatment of occlusive vascular diseases. Here, we investigated whether DN200434, an orally available estrogen receptor-related gamma inverse agonist, inhibits proliferation and migration of VSMCs and neointima formation by suppressing mitochondrial oxidative phosphorylation. Methods: VSMCs were isolated from the thoracic aortas of 4-week-old Sprague-Dawley rats. Oxidative phosphorylation and the cell cycle were analyzed in fetal bovine serum (FBS)- or platelet-derived growth factor (PDGF)-stimulated VSMCs using a Seahorse XF-24 analyzer and flow cytometry, respectively. A model of neointimal hyperplasia was generated by ligating the left common carotid artery in male C57BL/6J mice. Results: DN200434 inhibited mitochondrial respiration and mammalian target of rapamycin complex 1 activity and consequently suppressed FBS- or PDGF-stimulated proliferation and migration of VSMCs and cell cycle progression. Furthermore, DN200434 reduced carotid artery ligation-induced neointima formation in mice. Conclusion Our data suggest that DN200434 is a therapeutic option to prevent the progression of atherosclerosis.

Background/Aims: We aimed to define an optimal target population and drug-specific biomarkers that may predict dipeptidyl peptidase (DPP)-4 inhibitor responses in non-alcoholic fatty liver disease (NAFLD). Methods: An exploration study (study I) was performed using three different NAFLD models (basket study design; high-fat diet [HFD], methionine choline-deficient diet [MCD], and high-cholesterol Western diet [WD] models). RNA transcriptome analysis was performed on pre-studied liver tissues to identify biomarkers that could predict the response to DPP-4 inhibitors. In the validation study (study II), the HFD-induced NAFLD model was divided into high and low hepatic insulin-like growth factor binding protein 1 (Igfbp-1) groups based on the pre-study liver biopsy. Results: DPP-4 inhibitor attenuated the NAFLD activity score and fibrosis stage in the HFD model but not in the WD and MCD models. The overall response rate was 19% across the modified basket NAFLD trial and 42%, 25%, and 0% in the HFD, WD, and MCD models. Hepatic Igfbp-1 expression was higher in the responder group than in the non-responder group in pre-study biopsy samples. In contrast, hepatic Igfbp-1 expression was lower in the responder group than in the non-responder group in the end-study biopsy samples. DPP-4 inhibitor response rates were 83% and 17% in the baseline hepatic high Igfbp-1 and low Igfbp-1 groups, respectively. Hepatic messenger RNA Igfbp-1 expression was positively correlated with serum IGFBP-1 levels. Conclusions The DPP-4 inhibitor response was higher in the HFD phenotype and pre-treatment levels of hepatic or serum IGFBP-1 were high.

The main benefit of proton therapy over photon beam radiotherapy is the absence of exit dose, which offers the opportunity for highly conformal dose distributions to target volume while simultaneously irradiating less normal tissue. For proton beam therapy two patient specific beam modifying devices are used. The aperture is used to shape the transverse extension of the proton beam to the shape of the tumor target and a patient-specific compensator attached to the block aperture when required and used to modify the beam range as required by the treatment plan for the patient. A block of range shifting material, shaped on one face in such a way that the distal end of the proton field in the patient takes the shape of the distal end of the target volume. The mechanical quality assurance of range compensator is an essential procedure to confirm the 3 dimensional patient-specific dose distributions. We proposed a new quality assurance method for range compensator based on image processing using X-ray tube of proton therapy treatment room. The depth information, boundaries of each depth of plan compensatorfile and x-ray image of compensator were analyzed and presented over 80% matching results with proposed QA program.
Humans ; Proton Therapy ; Protons

This study examined the dosimetric influence of implanted gold markers in proton therapy and the effects of their positions in the spread-out Bragg peak (SOBP) proton beam. The implanted cylindrical gold markers were 3 mm long and 1.2 mm in diameter. The dosimetric influence of the gold markers was determined with markers at various locations in a proton-beam field. Spatial dose distributions were measured using a three-dimensional moving water phantom and a stereotactic diode detector with an effective diameter of 0.5 mm. Also, a film dosimetry was performed using Gafchromic External Beam Treatment (EBT) film. The GEANT4 simulation toolkit was used for Monte-Carlo simulations to confirm the measurements and to construct the dose-volume histogram with implanting markers. Motion data were obtained from the portal images of 10 patients to investigate the effect of organ motions on the dosimetric influence of markers in the presence of a rectal balloon. The underdosed volume due to a single gold marker, in which the dose was less than 95% of a prescribed amount, was 0.15 cc. The underdosed volume due to the presence of a gold marker is much smaller than the target volume. However, the underdosed volume is inside the gross tumor volume and is not smeared out due to translational prostate motions. The positions of gold markers and the conditions of the proton-beam field give different impacts on the dose distribution of a target with implanted gold markers, and should be considered in all clinical proton-based therapies.
Film Dosimetry ; Humans ; Prostate ; Prostatic Neoplasms ; Proton Therapy ; Protons ; Tumor Burden ; Water

TomoTherapy has a merit to treat cancer with Intensity modulated radiation and combines precise 3-D imaging from computerized tomography (CT scanning) with highly targeted radiation beams and rotating beamlets. In this paper, we comparing the dose distribution between TomoTherapy and linear accelerator based intensity modulated radiotherapy (IMRT) for 10 Head & Neck patients using TomoTherapy which is newly installed and operated at National Cancer Center since Sept. 2006. Furthermore, we estimate how the homogeneity and Normal Tissue Complication Probability (NTCP) are changed by motion of target. Inverse planning was carried out using CadPlan planning system (CadPlan R.6.4.7, Varian Medical System Inc. 3100 Hansen Way, Palo Alto, CA 94304-1129, USA). For each patient, an inverse IMRT plan was also made using TomoTherapy Hi-Art System (Hi-Art2_2_4 2.2.4.15, TomoTherapy Incorporated, 1240 Deming Way, Madson, WI 53717-1954, USA) and using the same targets and optimization goals. All TomoTherapy plans compared favorably with the IMRT plans regarding sparing of the organs at risk and keeping an equivalent target dose homogeneity. Our results suggest that TomoTherapy is able to reduce the normal tissue complication probability (NTCP) further, keeping a similar target dose homogeneity.
Head ; Humans ; Imaging, Three-Dimensional ; Neck ; Organs at Risk ; Particle Accelerators ; Radiotherapy, Intensity-Modulated

Hemorrhage into the esophagus due to aortoesophageal communication is very rare but life-threatening with high morbidity and mortality. Because of this, most cases of aortoesophageal fistula are confirmed by autopsy. However, we report herein a case of a 62-year-old male with an aortoesophageal fistula who was successfully treated with endovascular stent-grafting. The patient had undergone esophageal stent insertion due to esophageal cancer and experienced hematemesis and hemodynamic shock due to an aortoesophageal fistula. Emergency endoscopy was unable to identify the source of the hemorrhage due to massive bleeding. Computed tomography of the chest revealed a focal pseudoaneurysm at the descending aorta and diffuse thinning of the esophageal wall, which were treated with endovascular stent-grafting. Although aortoesophageal fistulas are usually fatal, implantation of a covered stent into the esophagus may help prevent massive bleeding, providing valuable time to treat the patient.
Aneurysm, False ; Aorta, Thoracic ; Autopsy ; Blood Vessel Prosthesis* ; Emergencies ; Endoscopy ; Esophageal Neoplasms* ; Esophagus ; Fistula* ; Hematemesis ; Hemodynamics ; Hemorrhage ; Humans ; Male ; Middle Aged ; Mortality ; Shock ; Stents ; Thorax