산전 발프론산 노출 자폐 백서 모델에서의 뇌 활성 및 연결성

Dept. of Medical Science/박사Autism spectrum disorder (ASD) is a severe lifelong neurodevelopmental disorder characterized by early-onset impairments in social communication and social interaction, and restrictive and repetitive behavior, interests, or activities. Currently no biological markers are available to make a reliable diagnosis of ASD. I used valproic acid (VPA) rat model to explore the possible alterations in metabolic brain activity and connectivity. Female Sprague Dawley rats were given a single intraperitoneal injection of sodium valproate or normal saline on embryonic day 12.5. To evaluate autistic-like behaviors in pups, social interaction was examined during postnatal weeks 4-6 using three-chamber social approach test. Resting-state 18F-fluorodeoxyglucose (FDG) positron emission tomography (PET) scans were acquired at postnatal weeks 6 or 62. To assess the changes in metabolic brain activity by VPA treatment, Statistical Parametric Mapping (SPM) was performed. I also examined if change in metabolic brain connectivity was accompanied with alterations of regional metabolic activity. Metabolic connectivity was modeled using both conventional correlation analysis, and sparse inverse covariance estimation (SICE), a partial correlation analysis. VPA-treated rats exhibited impairments in social behaviors, and this difference was more pronounced in male than female rats. Preference for social novelty was impaired in VPA-treated male rats, while sociability was diminished in VPA-treated female rats. I found that metabolic activity and connectivity was significantly changed by VPA treatment. Changes in metabolic connectivity was revealed by SICE while conventional correlation analysis did not show any difference. VPA-treated male rats had significantly decreased metabolic activity in the olfactory bulb, and had decreased metabolic connectivity between the left insular cortex and left amygdala, which constitute the salience network. There were no brain regions with decreased metabolic activity in VPA-treated female rats. In contrast, VPA-treated female rats had reduced metabolic connectivity between the thalamus and midbrain, and between the right medial prefrontal cortex and left caudoputamen. Such alterations in metabolic activity and connectivity may represent neurobiological substrates of autistic-like behavior, particularly in males, and may serve as a pathognomonic sign in VPA rat models of ASD. As such this study supports the idea that non-invasive brain imaging may serve as an imaging endophenotype that could aid diagnosis of ASD, classification of severity, and possibly reveal insights to neurobiological underpinnings in autistic-like behavior. 자폐스펙트럼장애는 일생 동안 지속되는 심한 신경발생학적 장애로, 조기에 사회적 의사소통과 사회적 상호작용에 저하가 발생하고, 제한적이고 반복적인 행동이 나타나는 것이 특징이다. 현재 진단에 유용한 생물학적 표지자는 알려진 것이 없다. 발프론산 백서 모델을 사용하여 뇌 대사 및 연결성에 변화가 존재하는지 알아보았다. 암컷 백서(female Sprague Dawley rat)에 임신 후 12.5일에 발프론산 또는 생리 식염수를 복강 내에 주사하였다. 새끼 백서에서 자폐 행동을 평가하기 위하여 행동 검사(three-chamber social approach test)를 생후 4-6주에 시행하였다. 기저 상태 18F-FDG 양전자방출단층촬영(18F-fluorodeoxyglucose positron emission tomography)을 생후 6주 또는 62주에 시행하였고, 뇌 대사에 변화가 있는지 알아보기 위하여 SPM(Statistical Parametric Mapping)을 시행하였다. 또한 대사 연결성 변화가 동반되는지 확인하였다. 대사 연결성은 전통적인 상관 분석, 그리고 부분 상관 분석 기법인 SICE(sparse inverse covariance estimation)를 이용하여 분석하였다. 발프론산에 노출된 백서는 사회적 행동이 저하되었으며, 이 차이는 암컷 백서보다 수컷 백서에서 두드러지게 나타났다. 수컷 백서에서는 사회적 새로움 선호(preference for social novelty)가 감소하였고, 암컷 백서에서는 사회성(sociability)이 감소하였다. 발프론산에 노출된 백서에서 대사 활성도 및 대사 연결성에 변화가 나타나는 것을 확인하였다. 대사 연결성 변화는 전통적인 상관 분석으로는 확인할 수 없었고, SICE로 확인할 수 있었다. 발프론산에 노출된 수컷 백서에서 후각망울(olfactory bulb)에서 대사가 유의하게 감소하였고, 현저성 망(salience network)을 구성하는 좌도피질(left insular cortex)과 좌편도(amygdala) 사이에 대사 연결성이 감소하였다. 발프론산에 노출된 암컷 백서에서는 대사 활성도가 감소한 부분이 없었으나 시상(thalamus)과 중뇌(midbrain), 그리고 우내측전전두엽피질(right medial prefrontal cortex)과 꼬리조가비핵(caudoputamen) 사이의 대사적 연결성이 감소하였다. 이러한 대사 활성도 및 대사 연결성 변화는 특히 남성에서 자폐 유사 행동에 대한 신경생물학적인 기질을 대변할 수 있을 것으로 보이며, 발프론산 노출 자폐 모델에서 질병 특유 징후로서 가능성이 있음을 시사한다. 따라서 본 연구는 비침습적...ope

비모수적 방법을 이용한 공간검색통계량

의학전산통계학 협동과정/석사지리학적 공간 역학이나 질병 감시 연구에서 공간 검색 통계 방법은 공간 데이터에서 결과 변수의 비율이 현저하게 높거나 낮은 특정 군집을 찾아내고 통계학적 유의성을 평가한다. 기존의 연구 방법들은 자료가 어떠한 분포 가정을 따른다고 생각하는 모수적 방법이다. 하지만 자료가 해당 분포를 따르지 않고 비대칭적 분포나 꼬리가 두꺼운 분포를 따르는 경우에는 분포 가정이 적합하지 않으므로 기존의 방법들을 적용시키기 어렵다. 그러므로 기존 Kulldorff, Huang, Konty (2009)가 제안한 normal 방법을 기반으로 분포 가정이 필요 없는 비모수적 방법을 적용하여 scanning window 안과 밖을 비교할 때 우도비 검정 대신 윌콕슨 순위합 검정을 사용한 방법을 제안한다. 자료가 비대칭적이거나 꼬리가 두꺼운 분포를 따를 때 기존에 제시된 대부분의 방법과 같이 모수 통계분석 방법을 사용하는 경우 검정력과 정확도가 떨어지는 문제점이 발생할 수 있다. 기존 normal 방법에서 정규분포를 따르지 않는 경우 검정력과 정확도를 확인해 본 바가 없으므로 본 논문에서 모의실험을 통해 여러 가지 분포 하에서 normal 방법과 비모수적 방법의 검정력, 정확도를 비교한다. 또한 우리나라 여성 유방암 사망률 자료에 비모수적 방법을 적용하여 기존 방법들을 적용한 결과와 비교해 본다. 모의실험 결과를 통해 자료가 비대칭적이거나 꼬리가 두꺼운 분포를 따를 경우에 normal 방법의 검정력과 정확도는 떨어지는 반면 비모수적 방법은 높게 유지되는 것을 확인하였다. 실제 자료 분석에서도 normal 방법과 weighted normal 방법으로 찾은 군집은 포아송 방법을 이용해서 찾아낸 군집과 일치하지 않고 유의성에도 차이를 보였지만 비모수적 방법은 비슷한 군집을 찾았고 유의성 또한 일치하였다. 이를 통해 연속적 자료의 분포가 비대칭적이거나 꼬리가 두꺼운 경우에는 비모수적 방법을 사용하는 것이 검정력과 정확도를 높일 수 있는 방법이 될 것으로 기대된다.ope

Changes in brain metabolic connectivity underlie autistic-like social deficits in a rat model of autism spectrum disorder

The neurobiological basis of social dysfunction and the high male prevalence in autism spectrum disorder (ASD) remain poorly understood. Although network alterations presumably underlie the development of autistic-like behaviors, a clear pattern of connectivity differences specific to ASD has not yet emerged. Because the heterogeneous nature of ASD hinders investigations in human subjects, we explored brain connectivity in an etiologically homogenous rat model of ASD induced by exposure to valproic acid (VPA) in utero. We performed partial correlation analysis of cross-sectional resting-state 18F-fluorodeoxyglucose positron emission tomography scans from VPA-exposed and control rats to estimate metabolic connectivity and conducted canonical correlation analysis of metabolic activity and behavior scores. VPA-treated rats exhibited impairments in social behaviors, and this difference was more pronounced in male than female rats. Similarly, current analyses revealed sex-specific changes in network connectivity and identified distinct alterations in the distributed metabolic activity patterns associated with autistic-like social deficits. Specifically, diminished activity in the salience network and enhanced activity in a cortico-cerebellar circuit correlated with the severity of social behavioral deficits. Such metabolic connectivity features may represent neurobiological substrates of autistic-like behavior, particularly in males, and may serve as a pathognomonic sign in the VPA rat model of ASD.ope

Prognosis Associated with Glycolytic Activity in Regional Lymph Nodes of Patients with Previously Untreated Metastatic Breast Cancer: A Preliminary Study

Better mechanisms of predicting prognoses in patients with metastatic breast cancer will improve the identification of patients for whom curative treatments may be the most effective. In this study, the prognostic value of 18F-fluorodeoxyglucose positron emission tomography/computed tomography (18F-FDG PET/CT) was assessed in patients with metastatic breast cancer. A retrospective analysis of women who underwent 18F-FDG PET/CT for staging of newly diagnosed metastatic breast cancer was conducted. In each patient, the maximum standardized uptake value (SUV) and total lesion glycolysis (TLG) of primary tumors and regional lymph nodes were measured and analyzed for association with survival using the Cox proportional hazards regression model. From 346 consecutive patients, 32 with metastatic invasive ductal carcinoma of the breast were included in the study. The median duration of follow-up was 22.5 months. Disease progression occurred in 26 patients, and 11 patients died. When multivariate analyses with a stepwise forward regression were applied, only the maximum SUV and TLG of regional lymph nodes showed a significant correlation with progression-free survival and overall survival, respectively. This study demonstrates that increased 18F-FDG uptake in regional lymph nodes is a strong independent predictor of survival in women with metastatic invasive ductal carcinoma of the breast.ope

Prognostic values of mid-radiotherapy 18F-FDG PET/CT in patients with esophageal cancer

BACKGROUND: To identify whether early metabolic responses as determined using 18F-fluorodeoxyglucose positron emission tomography/computed tomography (FDG PET/CT) during radiotherapy (RT) predict outcomes in patients with esophageal cancer. METHODS: Twenty-one patients with esophageal cancer who received pre-treatment 18F-FDG PET/CT (PET1) and inter-fractional 18F-FDG PET/CT (PET2) after 11 fractions of RT (median 23.1 Gy, 2.1 Gy per fraction) were retrospectively reviewed. The region of interest for each calculation was delineated using "PET Edge". We calculated PET parameters including maximum and mean standardized uptake values (SUVmax and SUVmean, respectively), metabolic tumor volume (MTV), and total lesion glycolysis (TLG). The relative changes (%) were calculated using the logarithmically transformed parameter values for the PET1 and PET2 scans. Multivariate analysis of locoregional recurrence and distant failures were performed using Cox regression analysis. After identifying statistically significant PET parameters for discriminating responders from non-responders, receiver operating characteristics curve analyses were used to assess the potentials of the studied PET parameters. RESULTS: After a median follow-up of 13 months, the 1-year overall and progression-free survival rates were 79.0% and 34.4%, respectively. Four patients developed locoregional recurrences (LRRs) and 8 had distant metastases (DMs). The 1-year overall LRR-free rate was 76.9% while the DM-free rate was 60.6%. The relative changes in MTV (ΔMTV) were significantly associated with LRR (p = 0.03). Conversely, the relative changes in SUVmean (ΔSUVmean) were associated with the risk of DM (p = 0.02). An ΔMTV threshold of 1.14 yielded a sensitivity of 60%, specificity of 94%, and an accuracy of 86% for predicting an LRR. Additionally, a ΔSUVmean threshold of a 35% decrease yielded a sensitivity of 67%, specificity of 83%, and accuracy of 76% for the prediction DM. TRIAL REGISTRATION: Retrospectively registered. CONCLUSIONS: Changes in tumor metabolism during RT could be used to predict treatment responses, recurrences, and prognoses in patients with esophageal cancer.ope

PKC phosphorylation regulates mGluR5 trafficking by enhancing binding of Siah-1A.

Glutamate is the major excitatory neurotransmitter in the mammalian CNS and acts on both ionotropic and metabotropic glutamate receptors (mGluRs). The mGluRs are widely distributed in the CNS and modulate a variety of neuronal processes, including neurotransmitter release and ion channel function. In hippocampus and cortex, mGluR5 is highly expressed and plays an important role in the regulation of synaptic plasticity. Calmodulin (CaM) binding dynamically regulates mGluR5 surface expression; however, the mechanisms linking CaM to mGluR5 trafficking are not clear. Recent studies showed that CaM binding to mGluR7 regulates its trafficking in a phosphorylation-dependent manner by disrupting the binding of protein interacting with C kinase 1. The E3 ligase seven in absentia homolog (Siah)-1A binds to mGluR5 and competes with CaM binding, making it an intriguing molecule to regulate phosphorylation-dependent trafficking of mGluR5. In the present study, we find that CaM competes with Siah-1A for mGluR5 binding in a phosphorylation-dependent manner in rat hippocampal neurons. Specifically, phosphorylation of mGluR5 S901 favors Siah-1A binding by displacing CaM. We identified critical residues regulating Siah-1A binding to mGluR5 and showed that binding is essential for the Siah-1A effects on mGluR5 trafficking. Siah-1A binding decreases mGluR5 surface expression and increases endosomal trafficking and lysosomal degradation of mGluR5. Thus CaM-regulated Siah-1A binding to mGluR5 dynamically regulates mGluR5 trafficking. These findings support a conserved role for CaM in regulating mGluR trafficking by PKC-dependent regulation of receptor-binding proteinsope

Development and Testing of a Machine Learning Model Using 18F-Fluorodeoxyglucose PET/CT-Derived Metabolic Parameters to Classify Human Papillomavirus Status in Oropharyngeal Squamous Carcinoma

Objective: To develop and test a machine learning model for classifying human papillomavirus (HPV) status of patients with oropharyngeal squamous cell carcinoma (OPSCC) using 18F-fluorodeoxyglucose (18F-FDG) PET-derived parameters in derived parameters and an appropriate combination of machine learning methods in patients with OPSCC. Materials and methods: This retrospective study enrolled 126 patients (118 male; mean age, 60 years) with newly diagnosed, pathologically confirmed OPSCC, that underwent 18F-FDG PET-computed tomography (CT) between January 2012 and February 2020. Patients were randomly assigned to training and internal validation sets in a 7:3 ratio. An external test set of 19 patients (16 male; mean age, 65.3 years) was recruited sequentially from two other tertiary hospitals. Model 1 used only PET parameters, Model 2 used only clinical features, and Model 3 used both PET and clinical parameters. Multiple feature transforms, feature selection, oversampling, and training models are all investigated. The external test set was used to test the three models that performed best in the internal validation set. The values for area under the receiver operating characteristic curve (AUC) were compared between models. Results: In the external test set, ExtraTrees-based Model 3, which uses two PET-derived parameters and three clinical features, with a combination of MinMaxScaler, mutual information selection, and adaptive synthetic sampling approach, showed the best performance (AUC = 0.78; 95% confidence interval, 0.46-1). Model 3 outperformed Model 1 using PET parameters alone (AUC = 0.48, p = 0.047) and Model 2 using clinical parameters alone (AUC = 0.52, p = 0.142) in predicting HPV status. Conclusion: Using oversampling and mutual information selection, an ExtraTree-based HPV status classifier was developed by combining metabolic parameters derived from 18F-FDG PET/CT and clinical parameters in OPSCC, which exhibited higher performance than the models using either PET or clinical parameters alone.ope

유방암 환자에서 새로운 integrin 결합 양전자방출단층촬영 추적자, 18F-RGD-K5의 최초 임상 시험: 18F-FDG 섭취 및 미세혈관농도와의 비교

Dept. of Medicine/석사The purpose of this study was to evaluate the biodistribution and dosimetry of a newly developed integrin binding agent, 18F-RGD-K5, in healthy volunteers, and to compare the uptake pattern of 18F-RGD-K5 with 18F-FDG and microvessel density (MVD) in tumor specimen in patients with breast cancer. Methods: Four female healthy volunteers underwent five successive dynamic 18F-RGD-K5 PET scans and radiation absorbed doses were calculated. Eleven patients with primary or metastatic breast cancer underwent 18F-FDG and 18F-RGD-K5 PET scans. Biopsy specimen was obtained in 9 patients and immunohistochemistry using a mouse monoclonal antibody against CD31 was performed. In vitro 18F-FDG and 18F-RGD-K5 uptake and western blot analysis in breast cancer cell lines MCF-7 and MDA-MB-231 were also examined. Results: The radiation dose from 18F-RGD-K5 is similar to the dose from 18F-FDG and other 18F-based imaging agents. In 11 patients, a total of 189 lesions were identified on 18F-FDG PET scan, and 166 lesions (87.8%) showed increased 18F-RGD-K5 uptake. In comparison with 18F-RGD-K5 uptake, 18F-FDG uptake was higher in 108 lesions, and similar in 56 lesions. In 2 lesions, however, 18F-RGD-K5 uptake was higher. Although statistically insignificant, a weak correlation was observed between SUVs of 18F-RGD-K5 and MVD (r=0.43; P=0.25). No correlation was found between SUVs of 18F-RGD-K5 and 18F-FDG, or microvessel area. In vitro experiments showed that integrin β3 protein was more highly expressed in more aggressive MDA-MB-231 cells than in MCF-7 cells. However, 18F-RGD-K5 uptake was higher in MCF-7 cells than in MDA-MB-231 cells. These data suggest that 18F-RGD-K5 might recognize not only integrin αvβ3 but also other integrin subtypes, or a subpopulation of integrin αvβ3. Conclusion: Although 18F-RGD-K5 uptake was not well correlated with MVD, it is a safe and useful marker for noninvasive visualization of integrin expression in patients with breast cancer.restrictio

Effect of sandblasting, grinding and polishing on the shear bond strength of zirconia layered with porcelain

치의학과/석사[한글] 심미에 대한 환자의 요구가 증가하면서 전부도재관의 사용이 점차 증가하고 있다. 특히 지르코니아는 빛의 투과를 어느정도 허용하면서도 강도가 매우 뛰어나 금속-도재 수복물의 금속을 대체할 수 있는 재료로 기대되면서 최근 그 사용이 계속 확대되고 있다. 그러나 지르코니아 코어를 이용한 전부도재관 역시 다른 도재 수복물과 마찬가지로 항상 상부 도재의 파절과 도재와 지르코니아 사이에서의 파절이라는 위험성을 가지고 있다. 따라서 지르코니아-도재 수복물에서 장기간의 안정적인 결과를 얻기 위해서는 지르코니아와 도재간에 우수한 결합을 얻는 것이 필수적이라고 할 수 있겠다. 본 실험에서는 지르코니아에 다양한 표면거칠기를 부여한 후 도재와의 전단결합강도의 측정을 통해 지르코니아 표면처리에 따른 결합력의 차이가 있는지 알아보고자 하였다. Lava(3M ESPE) 지르코니아 블럭을 네군으로 나누어 1, 2, 3군은 소결전 각각의 군별로 320, 600, 150grit sandpaper 로 표면을 polishing하고 4군은 소결후 sandblasting으로 표면거칠기를 부여한 후 그 위에 도재를 축성하여 시편을 제작하였다. 제작된 시편의 전단결합강도를 만능시험기로 측정하였고 파절면은 광학현미경으로 관찰하여 다음과 같은 결과를 얻었다. 1. 소결 전 지르코니아 표면에 거칠기를 부여한 1, 2, 3군의 경우 2군과 3군이 1군에 비해 전단결합강도가 높게 측정되었으나 통계적으로 유의한 차이는 없었다(p>0.05). 2. 소결 후 sandblasting으로 표면처리를 한 4군은 1, 2, 3군에 비하여 낮은 전단결합강도가 측정되었다. 하지만 Tukey's multiple comparison test 결과 1, 2군과는 통계적으로 유의한 차이가 없었으며 3군 보다는 유의하게 낮은 파절강도를 보였다(P<0.05). 3. 광학현미경 관찰시 1, 2, 3군의 경우 지르코니아 표면의 trace line에 일부 도재입자들이 남아 있는 adhesive fracture양상이 관찰되었으며 4군의 경우는 대부분 도재내에서 파절된 cohesive fracture양상을 보이는 complex failure양상을 보였다. [영문] The use of all-ceramic restorations has increased according to patients' demand for esthetics. As zirconia is expected to substitute for metal restorations due to the excellent strength and allows for light transmission, its indication has recently expanded. All-ceramic restorations using zirconia, however, carry a risk of fracture at the interface of zirconia core and veneering ceramics just as the other types of porcelain restorations do. It is, therefore, essential to obtain superior bond between the zirconia core and veneering ceramics. This experiment was aimed to investigate whether there are differences in shear bond strength at the zirconia-veneering ceramic interface after different zirconia surface treatments causing different surface roughnesses. Lava(3M ESPE) zirconia blocks were divided into 4 groups. Group 1,2 and 3 were polished with sandpaper of 320, 600 and 150 grit respectively, before sintering. Group 4 was sandblasted with 50 ㎛ particles after sintering. All the group was then veneered with ceramics(Lava Ceram dentine powder). They are tested for the shear bond strength in Intron(Instron 3366, Instron Corp., Nowood, MA, U.S.A) and the fractured surfaces were examined under a microscope (x100, x2000). The results were as follows 1. The group 2, 3 showed higher shear bond strength than the group 1 but there was no statistically significant difference (p > 0.05). 2. The group 4 which was sandblasted after sintering exhibited lower shear bond strength than the group 1, 2 and 3. Analyzed with Turkey's multiple comparison test, the group 4 was not statistically different from the group 1, 2 in shear bond strength whereas it showed statistically lower shear bond strength than the group 3 (p < 0.05). 3. Microscopic examination revealed adhesive fractures with ceramic particles remaining in trace lines on the zirconia surfaces in the group 1 ,2 and 3. Group 4 demonstrated complex failure with cohesive fractures in most cases.ope

Image Quality Enhancement Using Domain-specific Priors

DoctorThe development of sophisticated imaging technologies has made cameras being not only widely used in our daily lives, but also capable of imitating the functioning of the human eye. Despite the advances of imaging devices, however, there is still room for improving the quality of obtained images because imaging systems are not perfect and can introduce some amounts of distortion or artifacts in the signal at any time. As high quality images are frequently required for various graphics and vision applications, image quality enhancement to overcome the fundamental limits of photography is crucial and necessary. Image quality enhancement aims to improve the interpretability or perception of information in images for human viewers and provide better input for other image processing techniques. These days, as digital cameras have come into wide use, the effort of improving the image quality is mostly accomplished by computer software for digitally stored images. Accommodating their popularity, this thesis presents software-based image quality enhancement solutions for digital photographs. Recent studies for image quality enhancement mostly involve the development of image priors on top of a well-defined image restoration framework. Since image priors capture common properties of concerned images and help to cope with the ill-posed nature of the problem, the image prior knowledge plays a critical role in image quality enhancement. However, despite the success of image priors, general-purpose image priors are too weak to regularize a particular problem domain and often do not provide satisfactory results. To overcome the limitations, domain-specific priors that account for the characteristics of a problem domain have been getting more attention recently. As domain-specific priors explicitly consider domain knowledge, it is considered as the key to produce high quality results. In this thesis, we follow the trend that exploits domain-specific image priors for image quality enhancement. Specifically, this thesis includes the following topics: Text Image Deblurring Using Text-specific Properties - Previous blind image deconvolution approaches have difficulties when dealing with text images, since they rely on natural image statistics which do not respect the special properties of text images. In this work, we propose a novel text image deblurring method which takes into account the specific properties of text images as a domain-specific prior. Our method extends the commonly used optimization framework for image deblurring to allow domain-specific properties to be incorporated in the optimization process. High Dynamic Range Imaging Using Coded Electronic Shutter - Typical high dynamic range (HDR) imaging approaches based on multiple images have difficulties in handling moving objects and camera shakes, suffering from the ghosting effect and the loss of sharpness in the output HDR image. In this work, we propose an HDR imaging approach using the coded electronic shutter which can capture a scene with row-wise varying exposures in a single image. We specifically investigate the characteristics of the coded electronic shutter as domain-specific prior knowledge and utilize it to produce a desired HDR image without ghosting and blur artifacts. Vignetting Correction Using Radial Bright Channel Prior - Previous vignetting correction approaches require reference calibration images or multiple images of different intensity attenuation with known camera settings. In this work, we presents a radial bright channel prior for single image vignetting correction, derived from a statistical property of vignetting-free images. Exploiting the prior, we can effectively estimate and correct the vignetting effect of a given image