Factors influencing the development of artificial intelligence in orthodontics.

OBJECTIVES: Since developing AI procedures demands significant computing resources and time, the implementation of a careful experimental design is essential. The purpose of this study was to investigate factors influencing the development of AI in orthodontics. MATERIALS AND METHODS: A total of 162 AI models were developed, with various combinations of sample sizes (170, 340, 679), input variables (40, 80, 160), output variables (38, 76, 154), training sessions (100, 500, 1000), and computer specifications (new vs. old). The TabNet deep-learning algorithm was used to develop these AI models, and leave-one-out cross-validation was applied in training. The goodness-of-fit of the regression models was compared using the adjusted coefficient of determination values, and the best-fit model was selected accordingly. Multiple linear regression analyses were employed to investigate the relationship between the influencing factors. RESULTS: Increasing the number of training sessions enhanced the effectiveness of the AI models. The best-fit regression model for predicting the computational time of AI, which included logarithmic transformation of time, sample size, and training session variables, demonstrated an adjusted coefficient of determination of 0.99. CONCLUSION: The study results show that estimating the time required for AI development may be possible using logarithmic transformations of time, sample size, and training session variables, followed by applying coefficients estimated through several pilot studies with reduced sample sizes and reduced training sessions.

East Asian and Southern European craniofacial class III phenotype: two sides of the same coin?

OBJECTIVES: The skeletal class III phenotype is a heterogeneous condition in populations of different ethnicities. This study aimed to analyse the joint and ethnicity-specific clustering of morphological features in skeletal class III patients of Asian and European origins. MATERIALS AND METHODS: This cross-sectional study involved South Korean and Spanish participants who fulfilled the cephalometric, clinical, and ethnic-related selection criteria. Radiographic records were standardised, calibrated, and measured. A total of 54 skeletal variables were selected for varimax factorial analysis (VFA). Subsequently, a cluster analysis (CA) was performed (mixed method: k-means and hierarchical clustering). Method error and precision were assessed using ICC, Student's t-test, and the Dahlberg formula. RESULTS: A total of 285 Korean and Spanish participants with skeletal class III malocclusions were analysed. After performing VFA and CA, the joint sample revealed three global clusters, and ethnicity-specific analysis revealed four Korean and five Spanish clusters. Cluster_1_global was predominantly Spanish (79.2%) and male (83.01%) and was characterised by a predominantly mesobrachycephalic pattern and a larger cranial base, maxilla, and mandible. Cluster_2_global and Cluster_3_global were mainly South Korean (73.9% and 75.6%, respectively) and depicted opposite phenotypes of mandibular projection and craniofacial pattern. CONCLUSIONS: A distinct distribution of Spanish and South Korean participants was observed in the global analysis. Interethnic and interethnic differences were observed, primarily in the cranial base and maxilla size, mandible projection, and craniofacial pattern. CLINICAL RELEVANCE: Accurate phenotyping, reflecting the complexity of skeletal class III phenotype across diverse populations, is critical for improving diagnostic predictability and future personalised treatment protocols.

Early Prediction of Radiation-Induced Pulmonary Fibrosis Using Gastrin-Releasing Peptide Receptor-Targeted PET Imaging.

Early diagnosis of radiation-induced pulmonary fibrosis (RIPF) in lung cancer patients after radiation therapy is important. A gastrin-releasing peptide receptor (GRPR) mediates the inflammation and fibrosis after irradiation in mice lungs. Previously, our group synthesized a GRPR-targeted positron emission tomography (PET) imaging probe, [64Cu]Cu-NODAGA-galacto-bombesin (BBN), an analogue peptide of GRP. In this study, we evaluated the usefulness of [64Cu]Cu-NODAGA-galacto-BBN for the early prediction of RIPF. We prepared RIPF mice and acquired PET/CT images of [18F]F-FDG and [64Cu]Cu-NODAGA-galacto-BBN at 0, 2, 5, and 11 weeks after irradiation (n = 3-10). We confirmed that [64Cu]Cu-NODAGA-galacto-BBN targets GRPR in irradiated RAW 264.7 cells. In addition, we examined whether [64Cu]Cu-NODAGA-galacto-BBN monitors the therapeutic efficacy in RIPF mice (n = 4). As a result, the lung uptake ratio (irradiated-to-normal) of [64Cu]Cu-NODAGA-galacto-BBN was the highest at 2 weeks, followed by its decrease at 5 and 11 weeks after irradiation, which matched with the expression of GRPR and was more accurately predicted than [18F]F-FDG. These uptake results were also confirmed by the cell uptake assay. Furthermore, [64Cu]Cu-NODAGA-galacto-BBN could monitor the therapeutic efficacy of pirfenidone in RIPF mice. We conclude that [64Cu]Cu-NODAGA-galacto-BBN is a novel PET imaging probe for the early prediction of RIPF-targeting GRPR expressed during the inflammatory response.

Porphyrin-Based Brain Tumor-Targeting Agents: [64Cu]Cu-porphyrin and [64Cu]Cu-TDAP.

The aim of this study is to evaluate a radioactive metal complex platform for brain tumor targeting. Herein, we introduce a new porphyrin derivative, 5,10,15,20-(tetra-N,N-dimethyl-4-aminophenyl)porphyrin (TDAP), in which four N,N-dimethyl-4-p-phenylenediamine (DMPD) moieties are conjugated to the porphyrin labeled with the radiometal 64Cu. DMPD affected the pharmacokinetics of porphyrin in terms of retention time in vivo and tumor-targeting ability relative to those of unmodified porphyrin. [64Cu]Cu-TDAP showed stronger enhancement than [64Cu]Cu-porphyrin in U87MG glioblastoma cells, especially in the cytoplasm and nucleus, indicating its tumor-targeting properties and potential use as a therapeutic agent. In the subcutaneous and orthotopic models of brain-tumor-bearing mice, [64Cu]Cu-TDAP was clearly visualized in the tumor site via positron emission tomography imaging and showed a tumor-to-brain ratio as high as 13. [64Cu]Cu-TDAP deserves attention as a new diagnostic agent that is suitable for the early diagnosis and treatment of brain tumors.

Feasibility of Gd-Based prostate cancer targeted magnetic resonance agents using prostate specific membrane antigen.

The aim of this work was to evaluate Gd-FC705, a prostate-specific membrane antigen (PSMA)-targeted MRI contrast agent. The r1 and r2 relaxivities of Gd-FC705 are 5.94 mM-1s-1 and 17.77 mM-1s-1, respectively, in HSA solution (0.67 mM) at 3 T, which are higher than those of Gd-DOTA. Specific targeting efficacy was found with a 3-fold enhancement between PSMA-negative (PSMA-) and PSMA-positive (PSMA+) cells. The in vivo targeting and bio-distribution of Gd-FC705 were further confirmed using nude mice bearing PC3 human prostate cancer xenografts, which showed a 2-fold increase in the contrast-to-noise ratio (CNR) for PSMA+ tumors compared to PSMA- tumors 1 h post injection and a longer circulation time than Gd-DOTA. These results demonstrate that Gd-FC705 has great potential as a diagnostic agent for prostate cancer.

Time series analysis.

INTRODUCTION: This article describes a simple method of applying a time series analysis to sample data sets using a free and open statistical software program, Language R. METHODS: Records of new patients who visited 2 different university-affiliated orthodontic departments in 2 different countries were collected. Time series analysis was performed by applying Language R software. The data sets and codes were provided for tutorial and illustrative purposes. RESULTS: Using time series decomposition, the trend component and the seasonal variation were separated and visualized graphically. CONCLUSIONS: Time series analysis may be helpful to clinicians by providing a simple tool to evaluate patient characteristics and manage the practice.

In vivo evaluation of PEGylated-liposome encapsulating gadolinium complexes for gadolinium neutron capture therapy.

Gadolinium neutron capture therapy (GdNCT) is a form of binary radiotherapy. It utilizes nuclear reactions that occur when gadolinium-157 is irradiated with thermal neutrons, producing high-energy γ-rays and Auger electrons. Herein, we evaluate the potential of GdNCT for cancer treatment using PEGylated liposome incorporated with an FDA-approved MRI contrast agent. The clinical gadolinium complex (Gadovist®) was successfully encapsulated inside the aqueous core of PEGylated liposomes by repeated freeze and thaw cycling. At a concentration of 152 µM Gd, the Gd-liposome showed high cytotoxicity upon thermal-neutron irradiation. In animal experiments, when a CT26 tumor model was administered with Gd-liposomes (19 mg 157Gd per kg) followed by 20-min irradiation of thermal neutron at a flux of 1.94 × 104 cm-2 s-1, tumor growth was suppressed by 43%, compared to that in the control group, on the 23rd day of post-irradiation. After two-cycle GdNCT treatment at a 10-day interval, tumor growth was more efficiently retarded. On the 31st day after irradiation, the weight of the excised tumor in the GdNCT group (38 mg 157Gd per kg per injection) was only 30% of that of the control group. These results demonstrate the potential of GdNCT using PEGylated liposomes containing MRI contrast agents in cancer treatment.

Comparison of Five Conductivity Tensor Models and Image Reconstruction Methods Using MRI.

Imaging of the electrical conductivity distribution inside the human body has been investigated for numerous clinical applications. The conductivity tensors of biological tissue have been obtained from water diffusion tensors by applying several models, which may not cover the entire phenomenon. Recently, a new conductivity tensor imaging (CTI) method was developed through a combination of B1 mapping, and multi-b diffusion weighted imaging. In this study, we compared the most recent CTI method with the four existing models of conductivity tensors reconstruction. Two conductivity phantoms were designed to evaluate the accuracy of the models. Applied to five human brains, the conductivity tensors using the four existing models and CTI were imaged and compared with the values from the literature. The conductivity image of the phantoms by the CTI method showed relative errors between 1.10% and 5.26%. The images by the four models using DTI could not measure the effects of different ion concentrations subsequently due to prior information of the mean conductivity values. The conductivity tensor images obtained from five human brains through the CTI method were comparable to previously reported literature values. The images by the four methods using DTI were highly correlated with the diffusion tensor images, showing a coefficient of determination (R2) value of 0.65 to 1.00. However, the images by the CTI method were less correlated with the diffusion tensor images and exhibited an averaged R2 value of 0.51. The CTI method could handle the effects of different ion concentrations as well as mobilities and extracellular volume fractions by collecting and processing additional B1 map data. It is necessary to select an application-specific model taking into account the pros and cons of each model. Future studies are essential to confirm the usefulness of these conductivity tensor imaging methods in clinical applications, such as tumor characterization, EEG source imaging, and treatment planning for electrical stimulation.

Adalimumab improves cognitive impairment, exerts neuroprotective effects and attenuates neuroinflammation in an Aß1-40-injected mouse model of Alzheimer's disease.

The pathogenesis of Alzheimer's disease (AD) is associated with an increased inflammatory response via activated microglia and astrocytes. In the present study, we investigated whether treatment with the anti-tumor necrosis factor alpha (TNF-α) monoclonal antibody adalimumab can improve cognitive function and reduce AD pathology in Aß1-40-injected animal models of AD, as well as the mechanisms underlying the effects of treatment. Aß1-40-injected mice treated with adalimumab exhibited significant improvements in memory relative to mice injected with Aß1-40 alone, as well as decreases in beta secretase-1 (BACE1) protein expression and Aß1-40 plaques. In addition, adalimumab treatment significantly attenuated neuronal damage and neuroinflammation in Aß1-40-injected mice. Aß1-40-induced decreases in brain-derived neurotrophic factor (BDNF) expression were also attenuated by treatment with adalimumab. Our experiments further verified that the effects of adalimumab are mediated by nuclear factor kappa B (NF-κB) p65 signalling. Serine 536 residues of NF-κB p65, which is phosphorylated by TNF-α, increased along with the degradation of inhibitor of κB (IκB) in the hippocampus of Aß-injected mice, although these effects were again attenuated by adalimumab. Furthermore, Aß1-40-induced increases in TNF-α and interleukin (IL)-6 expression were decreased by treatment with adalimumab. Our results indicate that adalimumab may be clinically useful in human patients with AD.

Additional increased effects of mannitol-temozolomide combined treatment on blood-brain barrier permeability.

The blood-brain barrier (BBB) is major obstacle in drug or stem cell treatment in chronic stroke. We hypothesized that adding mannitol to temozolomide (TMZ) is a practically applicable method for resolving the low efficacy of intravenous mannitol therapy. In this study, we investigated whether BBB permeability could be increased by this combined treatment. First, we established a chronic ischemic stroke rat model and examined changes in leakage of Evans blue dye within a lesion site, and in expression of tight junction proteins (TJPs), by this combined treatment. Additionally, in an in vitro BBB model using trans-wells, we analyzed changes in diffusion of a fluorescent tracer and in expression of TJPs. Mannitol-TMZ combined treatment not only increased the amount of Evans blue dye within the stroke lesion site, but also reduced occludin expression in rat brain microvessels. The in vitro study also showed that combined treatment increased the permeability for two different-sized fluorescent tracers, especially large size, and decreased expression of TJPs, such as occludin and ZO-1. Increased BBB permeability effects were more prominent with combined than with single treatments. Mannitol-TMZ combined treatment induced a decrease of TJPs with a consequent increase in BBB permeability. This combined treatment is clinically useful and might provide new therapeutic options by enabling efficient intracerebral delivery of various drugs that could not otherwise be used to treat many CNS diseases due to their inability to penetrate the BBB.

Assessment of brain beta-amyloid deposition in transgenic mouse models of Alzheimer's disease with PET imaging agents 18F-flutemetamol and 18F-florbetaben.

BACKGROUND: Although amyloid beta (Aß) imaging is widely used for diagnosing and monitoring Alzheimer's disease in clinical fields, paralleling comparison between 18F-flutemetamol and 18F-florbetaben was rarely attempted in AD mouse model. We performed a comparison of Aß PET images between 18F-flutemetamol and 18F-florbetaben in a recently developed APPswe mouse model, C57BL/6-Tg (NSE-hAPPsw) Korl. RESULTS: After an injection (0.23 mCi) of 18F-flutemetamol and 18F-florbetaben at a time interval of 2-3 days, we compared group difference of SUVR and kinetic parameters between the AD (n = 7) and control (n = 7) mice, as well as between 18F-flutemetamol and 18F-florbetaben image. In addition, bio-distribution and histopathology were conducted. With visual image and VOI-based SUVR analysis, the AD group presented more prominent uptake than did the control group in both the 18F-florbetaben and 18F-flutemetamol images. With kinetic analysis, the 18F-florbetaben images showed differences in K1 and k4 between the AD and control groups, although 18F-flutemetamol images did not show significant difference. 18F-florbetaben images showed more prominent cortical uptake and matched well to the thioflavin S staining images than did the 18F-flutemetamol image. In contrast, 18F-flutemetamol images presented higher K1, k4, K1/k2 values than those of 18F-florbetaben images. Also, 18F-flutemetamol images presented prominent uptake in the bowel and bladder, consistent with higher bio-distribution in kidney, lung, blood and heart. CONCLUSIONS: Compared with 18F-flutemetamol images, 18F-florbetaben images showed prominent visual uptake intensity, SUVR, and higher correlations with the pathology. In contrast, 18F-flutemetamol was more actively metabolized than was 18F-florbetaben (Son et al. in J Nucl Med 58(Suppl 1):S278, 2017].

Synthesis and Evaluation of Manganese(II)-Based Ethylenediaminetetraacetic Acid-Ethoxybenzyl Conjugate as a Highly Stable Hepatobiliary Magnetic Resonance Imaging Contrast Agent.

In this study, we designed and synthesized a highly stable manganese (Mn2+)-based hepatobiliary complex by tethering an ethoxybenzyl (EOB) moiety with an ethylenediaminetetraacetic acid (EDTA) coordination cage as an alternative to the well-established hepatobiliary gadolinium (Gd3+) chelates and evaluated its usage as a T1 hepatobiliary magnetic resonance imaging (MRI) contrast agent (CA). This new complex exhibits higher r1 relaxivity (2.3 mM-1 s-1) than clinically approved Mn2+-based hepatobiliary complex Mn-DPDP (1.6 mM-1 s-1) at 1.5 T. Mn-EDTA-EOB shows much higher kinetic inertness than that of clinically approved Gd3+-based hepatobiliary MRI CAs, such as Gd-DTPA-EOB and Gd-BOPTA. In addition, in vivo biodistribution and MRI enhancement patterns of this new Mn2+ chelate are comparable to those of Gd3+-based hepatobiliary MRI CAs. The diagnostic efficacy of the new complex was demonstrated by its enhanced tumor detection sensitivity in a liver cancer model using in vivo MRI.

The combination of mannitol and temozolomide increases the effectiveness of stem cell treatment in a chronic stroke model.

BACKGROUND: The blood-brain barrier (BBB) presents a significant challenge to the therapeutic efficacy of stem cells in chronic stroke. Various methods have been developed to increase BBB permeability, but these are associated with adverse effects and are, therefore, not clinically applicable. We recently identified that combination drug treatment of mannitol and temozolomide improved BBB permeability in vitro. Here, we investigated whether this combination could increase the effectiveness of stem cell treatment in an animal model of chronic ischemic stroke. METHODS: Chronic stroke was induced in rats by middle cerebral artery occlusion (MCAo). After then, rats were administered human umbilical cord-derived mesenchymal stromal cells (hUC-MSCs) by intravenous injection with or without combination drug treatment of mannitol and temozolomide. To evaluate the therapeutic efficacy, behavioral and immunohistochemical tests were performed, and the differences among control, stem cell only, combination drug only and stem cell with combination drug treatment were analyzed. RESULTS: Although no hUC-MSCs were detected in any group, treatment with stem cells and combination drug of mannitol and temozolomide increased the intracerebral delivery of hCD63-positive microvesicles compared with stem cell only treatment. Furthermore, treatment with stem cells and drug combination ameliorated behavioral deficits and increased bromodeoxyuridine-, doublecortin- and Reca-1-positive cells in the perilesional area as compared with other groups. DISCUSSION: The combination drug treatment of mannitol and temozolomide allowed for the efficient delivery of hUC-MSC-derived microvesicles into the brain in a chronic stroke rat model. This attenuated behavioral deficits, likely by improving neural regeneration and angiogenesis. Thus, combination drug treatment of mannitol and temozolomide could be a novel therapeutic option for patients with chronic ischemic stroke.

Radiometallic Complexes of DO3A-Benzothiazole Aniline for Nuclear Medicine Theranostics.

To develop a radioactive metal complex platform for tumor theranostics, we introduced three radiopharmaceutical derivatives of 1,4,7,10-tetraazacyclododecane-1,4,7-trisacetic acid-benzothiazole aniline (DO3A-BTA, L1) labeled with medical radioisotopes for diagnosis (68Ga/64Cu) and therapy (177Lu). The tumor-targeting ability of these complexes was demonstrated in a cellular uptake experiment, in which 177Lu-L1 exhibited markedly higher uptake in HeLa cells than the 177Lu-1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid complex. According to in vivo positron emission tomography imaging, high accumulation of 68Ga-L1 and 64Cu-L1 was clearly visualized in the tumor site, while 177Lu-L1 showed therapeutic efficacy in therapy experiments. Consequently, this molecular platform represents a useful approach in nuclear medicine toward tumor-theranostic radiopharmaceuticals when 68Ga-L1 or 64Cu-L1 is used for diagnosis, 177Lu-L1 is used for therapy, or two of the compounds are used in conjunction with each other.

Laparoscopic Partial Sleeve Duodenectomy for the Infra-Ampullary Gastrointestinal Stromal Tumors of the Duodenum.

BACKGROUND: Although organ-preserving operations are regarded as effective strategies for duodenal gastrointestinal stromal tumors (GISTs), laparoscopic partial sleeve duodenectomy (lap PSD) has not been fully evaluated. The aims of this study were to evaluate the effectiveness and technical feasibility of lap PSD. STUDY DESIGN: Between January 2011 and March 2016, we reviewed 13 patients who underwent laparoscopic approach among 22 patients who underwent PSD. PSD for the infra-ampullary lesions was defined as infra-ampullary duodenal resection including the first portion of the jejunum. After resection, all patients underwent reconstruction via side-to-side duodenojejunostomy. RESULTS: The total mean operation time was 273 min (range 160-346 min), and estimated mean blood loss was 80 ml (range scanty-200 ml). One patient was converted to open laparotomy because of mesocolonic tumor involvement. The median postoperative hospital stay was 10.5 days (range 4-36 days). There were no postoperative mortalities. Postoperative complications included 2 instances of delayed gastric emptying (DGE), 1 duodenojejunostomy stricture, and 2 intestinal obstructions. No patient was treated with adjuvant therapy. One patient experienced hepatic metastasis 28 months after surgery during a mean follow-up period of 48.6 months. CONCLUSION: Lap PSD might be an oncologically effective strategy for duodenal GIST, and the laparoscopic approach is a technically feasible and appealing surgical modality in terms of safety and perioperative results. However, DGE and anastomosis strictures are concerns for postoperative complications, which need to be further investigated.

Preliminary PET Study of 18F-FC119S in Normal and Alzheimer's Disease Models.

To evaluate the efficacy of 18F-FC119S as a positron emission tomography (PET) radiopharmaceutical for the imaging of Alzheimer's disease (AD), we studied the drug absorption characteristics and distribution of 18F-FC119S in normal mice. In addition, we evaluated the specificity of 18F-FC119S for ß-amyloid (Aß) in the AD group of an APP/PS1 mouse model and compared it with that in the wild-type (WT) group. The behavior of 18F-FC119S in the normal mice was characteristic of rapid brain uptake and washout patterns. In most organs, including the brain, 18F-FC119S reached its maximum concentration within 1 min and was excreted via the intestine. Brain PET imaging of 18F-FC119S showed highly specific binding of the molecule to Aß in the cortex and hippocampus. The brain uptake and binding values for the AD group were higher than those for the WT group. These results indicated that 18F-FC119S would be a candidate PET imaging agent for targeting Aß plaque.

Evaluation of [(89)Zr]-Oxalate as a PET Tracer in Inflammation, Tumor, and Rheumatoid Arthritis Models.

To obtain an additional pharmacological agent for the diagnosis of inflammation, we investigated the medical use of (89)Zr-oxalate as a positron emission tomography (PET) probe for the in vivo imaging of inflammation and compared its efficacy to that of 2-deoxy-2-[(18)F]fluoro-d-glucose ([(18)F]FDG) and sodium [(18)F]fluoride. (89)Zr-oxalate exhibited observable higher uptake in a macrophage cell line than in tumor cells. The inflammatory lesions and tumors were clearly visualized by PET imaging and autoradiography using (89)Zr-oxalate. Compared to [(18)F]FDG and sodium [(18)F]fluoride, (89)Zr-oxalate demonstrated a high selectivity index to the tumor at an early time point after injection and to inflammation at a delayed time point after injection (24 h). Through histological examination, large numbers of macrophages and neutrophils were observed in the tumor lesions with the highest (89)Zr-oxalate uptake. In a rheumatoid arthritis (RA) mouse model, (89)Zr-oxalate demonstrated a high level of accumulation in inflammatory lesions. (89)Zr-oxalate is a new strategic tool for tumor imaging and inflammatory processes.

Improved tumor-targeting MRI contrast agents: Gd(DOTA) conjugates of a cycloalkane-based RGD peptide.

Two new MRI contrast agents, Gd-DOTA-c(RGD-ACP-K) (1) and Gd-DOTA-c(RGD-ACH-K) (2), which were designed by incorporating aminocyclopentane (ACP)- or aminocyclohexane (ACH)-carboxylic acid into Gd-DOTA (gadolinium-tetraazacyclo dodecanetetraacetic acid) and cyclic RGDK peptides, were synthesized and evaluated for tumor-targeting ability in vitro and in vivo. Binding affinity studies showed that both 1 and 2 exhibited higher affinity for integrin receptors than cyclic RGDyK peptides, which were used as a reference. These complexes showed high relaxivity and good stability in human serum and have the potential to improve target-specific signal enhancement in vivo MR images.

Comparison of individualized facial growth prediction models based on the partial least squares and artificial intelligence.

OBJECTIVES: To compare facial growth prediction models based on the partial least squares and artificial intelligence (AI). MATERIALS AND METHODS: Serial longitudinal lateral cephalograms from 410 patients who had not undergone orthodontic treatment but had taken serial cephalograms were collected from January 2002 to December 2022. On every image, 46 skeletal and 32 soft-tissue landmarks were identified manually. Growth prediction models were constructed using multivariate partial least squares regression (PLS) and a deep learning method based on the TabNet deep neural network incorporating 161 predictor, and 156 response, variables. The prediction accuracy between the two methods was compared. RESULTS: On average, AI showed less prediction error by 2.11 mm than PLS. Among the 78 landmarks, AI was more accurate in 63 landmarks, whereas PLS was more accurate in nine landmarks, including cranial base landmarks. The remaining six landmarks showed no statistical difference between the two methods. Overall, soft-tissue landmarks, landmarks in the mandible, and growth in the vertical direction showed greater prediction errors than hard-tissue landmarks, landmarks in the maxilla, and growth changes in the horizontal direction, respectively. CONCLUSIONS: PLS and AI methods seemed to be valuable tools for predicting growth. PLS accurately predicted landmarks with low variability in the cranial base. In general, however, AI outperformed, particularly for those landmarks in the maxilla and mandible. Applying AI for growth prediction might be more advantageous when uncertainty is considerable.

A multivalent peptide as an activator of hypoxia inducible factor-1α.

Hypoxia inducible factor-1α (HIF-1α) is a transcription factor found in mammalian cells under hypoxia. While HIF-1α in hypoxia translocates to the nucleus where it transcribes the target genes including vascular endothelial growth factor (VEGF) mRNA, HIF-1α is degraded under normoxia, which involves its proline hydroxylation and subsequent binding to the von Hippel-Lindau protein-Elongin B-Elogin C (VBC) complex. Previously, peptide inhibitors against this interaction between hydroxylated HIF-1α and VBC have been developed to stabilize the transcriptional activity of HIF-1α by preventing the degradation of the protein even under normoxia. Despite the specific inhibition by these peptides, their poor inhibition potency needs to be improved for further clinical application. In this work, we have designed and prepared a streptavidin-based multivalent peptide inhibitor against the HIF-1α-VBC complexation. We have evaluated the potency of the multivalent peptide in terms of stabilization of HIF-1α and the downstream effect. As the result, we have found that the inhibitor showed about 13-fold lowered IC50 value compared with that of the corresponding monovalent peptide, thereby activating HIF-1α and leading to up-regulation of VEGF protein at the cellular level.