Apurinic/apyrimidinic endonuclease 1 (APE1) is an enzyme responsible for the initial step in the base excision repair pathway and is known to be a potential drug target for treating cancers, because its expression is associated with resistance to DNA-damaging anticancer agents. Although several inhibitors already have been identified, the identification of novel kinds of potential inhibitors of APE1 could provide a seed for the development of improved anticancer drugs. For this purpose, we first classified known inhibitors of APE1. According to the classification, we constructed two distinct pharmacophore models. We screened more than 3 million lead-like compounds using the pharmacophores. Hits that fulfilled the features of the pharmacophore models were identified. In addition to the pharmacophore screen, we carried out molecular docking to prioritize hits. Based on these processes, we ultimately identified 1,338 potential inhibitors of APE1 with predicted binding affinities to the enzyme.
Antineoplastic Agents ; Classification ; DNA Repair ; Molecular Docking Simulation

More effective production of human insulin is important, because insulin is the main medication that is used to treat multiple types of diabetes and because many people are suffering from diabetes. The current system of insulin production is based on recombinant DNA technology, and the expression vector is composed of a preproinsulin sequence that is a fused form of an artificial leader peptide and the native proinsulin. It has been reported that the sequence of the leader peptide affects the production of insulin. To analyze how the leader peptide affects the maturation of insulin structurally, we adapted several in silico simulations using 13 artificial proinsulin sequences. Three-dimensional structures of models were predicted and compared. Although their sequences had few differences, the predicted structures were somewhat different. The structures were refined by molecular dynamics simulation, and the energy of each model was estimated. Then, protein-protein docking between the models and trypsin was carried out to compare how efficiently the protease could access the cleavage sites of the proinsulin models. The results showed some concordance with experimental results that have been reported; so, we expect our analysis will be used to predict the optimized sequence of artificial proinsulin for more effective production.
Computer Simulation ; DNA, Recombinant ; Humans* ; Insulin ; Molecular Dynamics Simulation* ; Proinsulin ; Protein Sorting Signals ; Trypsin

The objectives of this study were to observe normal peristalsis and mixing (or segmental movements) and to evaluate an acupuncture stimulation (ST-36 and BL-27) on the intestinal (duodenum) motility in normal dogs using duplex Doppler sonography. Fifteen healthy Beagle dogs were used for this experiment after the administration of warm saline and pellet feeding. The duodenal motility was examined using duplex Doppler sonography. Six hours after the pellet feeding, an electroacupuncture stimulation at ST-36 and BL-27 was applied and the duodenal motility was examined using duplex Doppler sonography pre-stimulation, during the stimulation and post-stimulation. After saline and pellet administration, the duplex Doppler sonograms showed 3 types of peristalsis and a mixing type (or segmental movement) of duodenum motility. In the peristalsis types, most yielded high-amplitude signals which had one high peak (type-1), two high peaks (type-2), and three high peaks (type-3) and lasted more than 1.3 seconds. Mixing type of duodenum motility had weak signals and were lasted more than 1.5 seconds. Among the peristalsis types, the type 1 and type 2 were predominant and the type 3 was rarely observed. The frequency of intestinal motility stimulated by ST-36 acupoint was increased during the acupuncture stimulation (20% increase compared to the basal value) and decreased (7% decrease compared to the basal value) after stimulation. The frequency of intestinal motility stimulated by BL-27 acupoint was decreased during the acupuncture stimulation (31% decrease compared to the basal value) and increased (18% increase compared to the basal value) after stimulation. There was a significant increase(p<0.01) between the value found in during and the post-stimulation tests. We conclude that duplex Doppler studies permit a graphic visualization of intestinal movements which can be qualitatively and quantitatively analyzed using this technique, it is possible to evaluate the gastrointestinal motility after an acupuncture stimulation.
Acupuncture Points ; Animals ; Dogs/*physiology ; Electroacupuncture/methods/*veterinary ; *Gastrointestinal Motility ; Intestine, Small/physiology/*ultrasonography ; Peristalsis ; Ultrasonography, Doppler, Duplex/methods/*veterinary

Depth of prostate volume from the skin can vary due to intra-fractional and inter-fractional movements, which may result in dose reduction to the target volume. Therefore we evaluated the feasibility of automated depth determination-based adaptive proton therapy to minimize the effect of inter-fractional movements of the prostate. Based on the center of mass method, using three fiducial gold markers in the prostate target volume, we determined the differences between the planning and treatment stages in prostate target location. Thirty-eight images from 10 patients were used to assess the automated depth determination method, which was also compared with manually determined depth values. The mean differences in prostate target location for the left to right (LR) and superior to inferior (SI) directions were 0.9 mm and 2.3 mm, respectively, while the maximum discrepancies in location in individual patients were 3.3 mm and 7.2 mm, respectively. In the bilateral beam configuration, the difference in the LR direction represents the target depth changes from 0.7 mm to 3.3 mm in this study. We found that 42.1%, 26.3% and 2.6% of thirty-eight inspections showed greater than 1 mm, 2 mm and 3 mm depth differences, respectively, between the planning and treatment stages. Adaptive planning based on automated depth determination may be a solution for inter-fractional movements of the prostate in proton therapy since small depth changes of the target can significantly reduce target dose during proton treatment of prostate cancer patients.
Humans ; Prostate ; Prostatic Neoplasms ; Proton Therapy ; Protons ; Skin

Depth of prostate volume from the skin can vary due to intra-fractional and inter-fractional movements, which may result in dose reduction to the target volume. Therefore we evaluated the feasibility of automated depth determination-based adaptive proton therapy to minimize the effect of inter-fractional movements of the prostate. Based on the center of mass method, using three fiducial gold markers in the prostate target volume, we determined the differences between the planning and treatment stages in prostate target location. Thirty-eight images from 10 patients were used to assess the automated depth determination method, which was also compared with manually determined depth values. The mean differences in prostate target location for the left to right (LR) and superior to inferior (SI) directions were 0.9 mm and 2.3 mm, respectively, while the maximum discrepancies in location in individual patients were 3.3 mm and 7.2 mm, respectively. In the bilateral beam configuration, the difference in the LR direction represents the target depth changes from 0.7 mm to 3.3 mm in this study. We found that 42.1%, 26.3% and 2.6% of thirty-eight inspections showed greater than 1 mm, 2 mm and 3 mm depth differences, respectively, between the planning and treatment stages. Adaptive planning based on automated depth determination may be a solution for inter-fractional movements of the prostate in proton therapy since small depth changes of the target can significantly reduce target dose during proton treatment of prostate cancer patients.
Humans ; Prostate ; Prostatic Neoplasms ; Proton Therapy ; Protons ; Skin

Stress induces degeneration of brain structures and functions. Particularly, hippocampus is sensitive to stressful stimulations. In the present study, the change of synaptic related molecules in the mouse dentate gyrus was examined with immunohistochemistry after restraint stress. We subjected mice to restraint stress for 6 h per day for 4 days. As a result, the number of Ki-67, a marker for proliferation, and doublecortin (DCX), a marker for neurogenesis, immunoreactive cells was decreased in the stress group. On the other hand, the intensity of calbindinD-28k, a marker of pre-existing granule cells, immunoreactivity was increased in the granule cell layer after 4 days restraint stress. As well as, the immunoreactivity of synaptic related molecules, postsynaptic density-95 (PSD-95), growth association protein-43 (GAP-43) and beta-NADPH-d reactivity were increased in the inner molecular layer of dentate gyrus after 4 days restraint stress. In conclusion, this study shows that repeated restraint stress suppresses neurogenesis in dentate gyrus and strengthens synaptic plasticity of existing granule cells.
Animals ; Brain ; Dentate Gyrus* ; Hand ; Hippocampus ; Immunohistochemistry ; Mice* ; Neurogenesis ; Plastics*

Transcranial Doppler (TCD) was carried out to determine the resistive index (RI) values of normal canine cerebral arteries and its reproducibility and to evaluate the change of cerebral vascular resistance following diuretics administration. RI values of rostral cerebral artery (RCA) were compared between fontanelle window and temporal window. Normal ranges and reproducibility of the RI values were examined in the rostal cerebral artery (RCA) and caudal cerebral artery (CCA). And after administration of diuretics, TCD-derived RI values were measured at RCA and CCA. Cerebral vascular RI values of RCA and CCA were 0.55 +/- 0.05 and 0.55 +/- 0.03 in the normal dogs, respectively. There was no significant difference of RI between male and female; between fontanelle window and temporal window. Reproducibility of RI measurements between intraobserver and interobserver were relatively high. The RI of RCA and CCA were significantly increased 15 minutes after mannitol administration (p<0.01) and returned to baseline values by 30 minutes, but it did not significantly change after furosemide and saline administration. The results suggest that TCD is a useful test which can obtain reproducible results from any window and has the advantage of detecting subtle changes in cerebral vascular resistance.
Animals ; Cerebral Arteries/drug effects/*ultrasonography ; Diuretics/pharmacology ; Dogs/*physiology ; Feasibility Studies ; Furosemide/pharmacology ; Mannitol/pharmacology ; Reference Values ; Reproducibility of Results ; Ultrasonography, Doppler/*veterinary ; Vascular Resistance/drug effects/*physiology

PURPOSE: The purpose of this study is to evaluate the accuracy of surgical stent according to the supported type. MATERIALS AND METHODS: 5 sets of dental models which have tooth supported edentulous area and tooth-tissue supported edentulous area were made. Dental model were scanned with model scanner, and CBCT was taken. CT data and model scan data were overlapped using In2Guide software, implant were virtually planned in the software. Surgical stents are fabricated by 3D printing. The implant fixture were installed using the surgical stent, CBCT were retaken. CBCT before surgery and after surgery were overlapped, and the differences (angle difference, coronal difference, apical difference) were evaluated using statistical analysis. RESULTS: In the assessment of the accuracy of surgical guides according to arch type, there are no statistically significant differences between maxilla and mandible. In the case of support type, tooth supported stents showed lower angle difference and length difference than tooth-tissue supported stents, which are statistically significant. CONCLUSION: Arch type does not affect the accuracy of surgical stents. But tooth support stents are more accurate than tooth-tissue support stents in the case of angle and length difference.
Dental Implants ; Dental Models ; Mandible ; Maxilla ; Printing, Three-Dimensional ; Prostheses and Implants ; Stents ; Tooth

Objective: To evaluate the trueness and precision of full-arch scans acquired using five intraoral scanners and investigate the factors associated with the dimensional accuracy of the intraoral scan data. Methods: Nine adult participants (mean age, 34.3 ± 8.3 years) were recruited. Four zirconium spheres (Ø 6 mm) were bonded to the canines and the molars. Following acquisition of reference scans using an industrial-grade scanner, five intraoral scanners, namely i500, CS3600, Trios 3, iTero, and CEREC Omnicam, were used to scan the arches. Linear distances between the four reference spheres were automatically calculated, and linear mixed model analysis was performed to compare the trueness and precision of the intraoral scan data among the different scanners. Results: The absolute mean trueness and precision values for all intraoral scanners were 76.6 ± 79.3 and 56.6 ± 52.4 µm, respectively. The type of scanner and the measured linear distances had significant effects on the accuracy of the intraoral scan data. With regard to trueness, errors in the intermolar dimension and the distance from the canine to the contralateral molar were greater with Omnicam than with the other scanners. With regard to precision, the error in the linear distance from the canine to the molar in the same quadrant was greater with Omnicam and CS3600 than with the other scanners. Conclusions The dimensional accuracy of intraoral scan data may differ significantly according to the type of scanner, with the amount of error in terms of trueness being clinically significant.

Objective: To evaluate the trueness and precision of full-arch scans acquired using five intraoral scanners and investigate the factors associated with the dimensional accuracy of the intraoral scan data. Methods: Nine adult participants (mean age, 34.3 ± 8.3 years) were recruited. Four zirconium spheres (Ø 6 mm) were bonded to the canines and the molars. Following acquisition of reference scans using an industrial-grade scanner, five intraoral scanners, namely i500, CS3600, Trios 3, iTero, and CEREC Omnicam, were used to scan the arches. Linear distances between the four reference spheres were automatically calculated, and linear mixed model analysis was performed to compare the trueness and precision of the intraoral scan data among the different scanners. Results: The absolute mean trueness and precision values for all intraoral scanners were 76.6 ± 79.3 and 56.6 ± 52.4 µm, respectively. The type of scanner and the measured linear distances had significant effects on the accuracy of the intraoral scan data. With regard to trueness, errors in the intermolar dimension and the distance from the canine to the contralateral molar were greater with Omnicam than with the other scanners. With regard to precision, the error in the linear distance from the canine to the molar in the same quadrant was greater with Omnicam and CS3600 than with the other scanners. Conclusions The dimensional accuracy of intraoral scan data may differ significantly according to the type of scanner, with the amount of error in terms of trueness being clinically significant.