Positional Patterns Among the Auriculotemporal Nerve, Superficial Temporal Artery, and Superficial Temporal Vein for use in Decompression Treatments for Migraine

This study aimed to clarify intersection patterns and points among the superficial temporal artery (STA), superficial temporal vein (STV), and auriculotemporal nerve (ATN) based on surface anatomical landmarks to provide useful anatomical information for surgical decompression treatments of migraine headaches in Asians. Thirty-eight hemifaces were dissected. The positional patterns among the ATN, STA, and STV were divided into three morphological types. In type I, the ATN ran toward the temporal region and superficially intersected the STA and STV (n = 32, 84.2%). In type II, the ATN ran toward the temporal region and deeply intersected the STA and STV (n = 4, 10.5%). In type III, the ATN ran toward the temporal region and deeply intersected the STV alone (n = 2, 5.3%). The intersection points of types II and III were 10.3 ± 5.6 mm (mean ± SD) and 10.4 ± 6.1 mm anterior and 42.1 ± 21.6 mm and 41.4 ± 18.7 mm superior to the tragus, respectively. The ATN superficially intersected the STA and STV in all the Korean cadaver, while the ATN deeply intersected the STA and STV in 15% of the Thai cadavers. The pattern of the ATN deeply intersecting the STA and STV was less common in present Asian populations than in previously-reported Caucasian populations, implying that migraine headaches (resulting from the STA and STV compressing the ATN) are less common in Asians.ope

간세포암에서 섬유아세포 유래 간세포성장인자와 MET-ERK1/2-AP1/SP1 신호전달에 의한 KRT19의 발현 조절

Dept. of Medical Science/박사Background: Keratin 19 (KRT19) has been shown to be a stem/progenitor marker of liver cells and poor prognostic factor for hepatocellular carcinoma (HCC). We recently reported that HCCs with abundant fibrous stroma (scirrhous HCC) show expression of KRT19. The regulatory mechanism of KRT19 in HCC, however, is not well understood. Materials and methods: We investigated regulatory mechanisms of KRT19 expression in HCC using an in vitro model of paracrine interactions between hepatic stellate cell (hTERT-HSC) and HCC cell lines (HepG2, SNU423). The regulatory axis of KRT19 was validated in tissue microarrays of human HCC tissue (n=339). Results: The hepatic stellate cell line (hTERT-HSC) upregulated transcriptional and translational levels of KRT19 in both HCC cell lines (HepG2, SNU423) via paracrine interaction. Conditioned media (CM) from hTERT-HSC upregulated KRT19 expression via activation of the MEK-ERK1/2 pathway. Hepatocyte growth factor (HGF) from the hTERT-HSC CM and subsequent activation of c-MET in the HCC cell lines were responsible for ERK1/2 activation and KRT19 upregulation. Luciferase reporter assay revealed that AP1 and SP1 binding sites in KRT19 promoter are important to transgene expression. AP1 family proteins, JUN and FOSL1, and SP1, which are downstream transcriptional activators of ERK1/2, were found to be activators of KRT19 gene expression. Multikinase inhibitors, including sorafenib and crizotinib, which inhibit MET and ERK1/2 pathways, eliminated the previously observed, CM-induced upregulation of KRT19. In human HCC tissue, the expression of KRT19 was correlated with MET and FOSL1 expression, as well as amounts of tumor fibrous stroma. Conclusion: The expression of KRT19 in HCC is regulated by fibrous tumor stroma therein via a HGF-MET-ERK1/2-AP1 and SP1 axis. Our results provide insights into the molecular background of aggressive, KRT19-positive HCC. Keratin 19 (KRT19)는 간의 줄기세포/전구세포 표지자이며, 간암의 불량한 예후를 나타내는 인자로 잘 알려져 있음. 본 연구진은 풍부한 섬유성 기질을 가진 간암의 아형 (경화성 간암)에서 KRT19의 발현이 높음을 보고한 바 있음. 그러나, 간암에서 KRT19의 발현 조절 기전은 잘 알려져 있지 아니함. 본 연구에서는 간성상세포주(hTERT-HSC)와 간암세포주(HepG2, SNU423) 사이의 분비 인자 상호 작용 모델을 이용하여 KRT19의 발현 조절 기전을 연구하였음. 또한 KRT19의 조절 기전을 인체 간암 조직 339례로 구성된 조직미세배열에서 검증하였음. 간성상세포주(hTERT-HSC)은 분비 인자를 통하여 두 간암세포주에서 KRT19의 전사 및 단백질 발현을 증가시켰음. hTERT-HSC 유래 적응용배지에 포함된 간세포성장인자가 MET을 활성화시키며, 이에 따라 활성화된 MEK-ERK1/2 신호전달계에 의하여 KRT19의 발현이 증가함. 루시페레이즈를 이용한 촉진염기서열 분석을 통하여 KRT19 촉진염기서열 중 AP1과 SP1 전사인자 결합부위가 KRT19 조절에 중요함을 밝힘. ERK1/2 신호전달계의 하위에 있는 JUN과 FOSL1 등의 AP1 전사인자와 SP1 전사인자가 KRT19의 발현을 활성함을 밝힘. Sorafenib, crizotininb이 MET 또는 MEK-ERK1/2 신호전달계의 활성을 저해하여 적응용배지에 의한 KRT19 발현 증가를 저해할 수 있었음. 인체 간암 조직에서 면역 염색으로 단백질 발현을 확인한 결과, KRT19의 발현은 HGF, MET, FOSL1의 발현과 유의한 상관 관계를 보였으며, 간암에서 관찰된 암 연관 섬유아세포 양과도 유의한 상관을 보였음. 결론적으로, 간암에서 KRT19의 발현은 간암의 암 연관 섬유아세포에 의하여 HGF-MET-ERK1/2-AP1/SP1 신호전달을 통하여 조절됨. 본 연구 결과는 임상적으로 불량한 예후를 보이는 KRT19 양성 간암의 분자적 특성을 이해할 수 있도록 함.ope

Spreading and Structural Reliability Analysis by Extraction of Hun Network with Gamma Distribution

학위논문 (박사)-- 서울대학교 대학원 : 생태조경.지역시스템공학부(지역시스템공학전공), 2014. 2. 이정재.실세계에서 계(System)는 전체 구조를 대표해주는 허브로 구성된 계와 배경처럼 모든 곳에서 동일한 무작위 계가 혼합되어 있다. 만약 대상에서 전체 구조를 대표할 수 있는 허브 계를 추출할 수 있다면 해석의 정확성과 효율성을 동시에 향상시킬 수 있을 것이다. 연속체로 구성된 계를 간단한 이산화 모델로 변화시켜 해석하는 경우의 네트워크도 앞에서 논한 바와 같이 절점이 불균등한 분포를 가지는 허브 네트워크와 절점이 균등하게 분포된 무작위 네트워크로 구분된다. 두 네트워크는 서로 다른 특성을 가지며 해석방법도 다르다. 따라서 본 연구에서는 실제 문제에서 대표성 있는 허브 네트워크를 추출하고, 그 허브 네트워크를 거시적 관점의 취약성 분석, 미시적 관점의 군집화 분석 등의 해석을 확산 및 구조 신뢰성 문제에 적용하여 고찰하였다. 모든 네트워크는 절점을 연결하는 연결선의 개수를 변수로 하는 경우 고유한 연결선의 분포를 가지게 된다. 이를 감마분포로 나타내면 분포의 고유값에 해당하는 형상계수와 규모계수를 구할 수 있다. 그리고 이 두 개의 고유값을 이용하면 대상 네트워크에서 허브 네트워크를 추출할 수 있는 임계치를 산정할 수 있다. 추출된 허브 네트워크는 불균등한 분포를 가지기 때문에 연결성에 따라서 절점들의 중요도가 달라진다. 많은 연결선을 가지는 허브 절점은 전체 네트워크의 규모에 결정적인 영향을 미치므로, 네트워크의 생성, 소멸과 같은 외적 변화를 살피는데 유용하다. 허브 탐색 방법을 가축전염병의 확산과 소멸에 적용하여 효율적으로 확산을 차단할 수 있는 방안에 대해서 고찰하였다. 외적으로 고정된 허브 네트워크에서 연결선의 속성이 확률적으로 변동하는 경우, 컨볼루션을 이용한 군집화를 통해서 전체 네트워크의 내부 변화를 고찰할 수 있다. 뼈대 구조에서 파괴에 영향을 주는 허브 네트워크를 군집화하여 효율적으로 구조 신뢰성을 적용하는 방안을 고찰하였다. 허브 네트워크의 추출과 취약성 분석 및 군집화 등과 같은 해석 방법을 구조 문제와 확산 문제에 각각 적용한 결과, 연속체에서 최적 구조 추출을 위한 수행지수와 비교할 때 각 단계별 변형에너지와 부피를 산정할 필요 없이 연결선 수 분포의 분석만으로 약 98% 이상의 정확도를 나타냈다. 그리고 뼈대 구조의 구조신뢰성 해석시 몬테카를로 해석과 같이 1,000,000번의 연산 없이 각 외력에 대한 한 번의 군집화 분석만으로 Beam, Sway 모드 파괴확률이 95%이상의 정확도를 가지는 것을 확인하였다. 가축전염병의 확산 문제에서는 허브네트워크를 추출하고 취약성 분석을 수행하여 전체의 12% 농가만을 차단하여 기존의 87% 농가를 차단하는 대책과 동일한 효과를 낼 수 있음을 확인하였다.제 1 장 서 론 1 1.1 연구배경 1 1.2 연구사 3 1.2.1 복잡계 네트워크 3 1.2.2 네트워크 추출 5 1.2.3 중심성 분석 6 1.2.3 군집화 분석 7 1.3 연구목적 및 범위 8 1.2.1 감마분포를 이용한 허브 네트워크 추출 8 1.2.2 허브 네트워크의 취약성 분석 9 1.2.3 확률을 이용한 허브 네트워크 10 1.4 연구구성 10 참고문헌 13 제 2 장 감마분포를 이용한 허브 네트워크 추출 17 2.1 서 론 17 2.2 혼합계의 네트워크 표현 19 2.3 감마 분포의 형상계수 시뮬레이션 22 2.3.1 무작위 네트워크 25 2.3.2 허브 네트워크 26 2.3.3 혼합 네트워크 27 2.4 혼합 네트워크의 허브 네트워크 추출 28 2.4.1 네트워크 이산 계층화 28 2.4.2 혼합 네트워크 임계치 30 2.5 이산 계층화 검증 33 2.6 소 결 36 참고문헌 38 제 3 장 허브 네트워크의 취약성 분석 41 3.1 서 론 41 3.2 허브 네트워크 취약성 분석 43 3.3 네트워크 취약성 분석을 이용한 확산 해석 45 3.3.1 네트워크 허브와 확산 46 3.3.2 모델의 적용 51 3.4 소 결 68 참고문헌 71 제 4 장 확률을 이용한 허브 네트워크 군집화 분석 75 4.1 서 론 75 4.2 확률 재규격화를 이용한 군집화 77 4.2.1 확률 재규격화 77 4.2.2 군집화 모델 개발 79 4.3 군집화 모델의 구현 및 고찰 86 4.3.1 CPC 모델의 구현 86 4.3.2 CPC 모델의 검증 93 4.3.3 기존 모델과 비교 95 4.4 소 결 97 참고문헌 99 제 5 장 허브 네트워크 추출과 분석 모델의 적용 103 5.1 연속체 구조물의 응력 흐름에 대한 군집화 적용 103 5.1.1 연속체 구조물의 이산화 103 5.1.2 허브 네트워크 추출과 진화론적 최적화 구조 기준 105 5.1.3 응력 흐름의 군집화 분석 110 5.2 뼈대 구조의 파괴 모드 해석 115 5.2.1 뼈대 구조에서 CPC 구현 117 5.2.2 뼈대 구조의 네트워크 치환 120 5.2.3 파괴 모드 해석 121 5.3 확산 네트워크의 추출과 취약성 분석 125 5.3.1 대상 자료 125 5.3.2 확산 네트워크의 추출 127 5.3.3 확산 네트워크의 취약성 분석 128 참고문헌 132 제 6 장 결 론 135 6.1 요약 및 결론 135 6.2 향후 연구 138 Abstract 141Docto

β-Catenin activated hepatocellular adenoma: a report of three cases in Korea

Hepatocellular adenoma (HCA) is an uncommon benign hepatic tumor, and the use of oral contraceptives is known to contribute to the development of HCA. Recently, a genotype and phenotype classification system for HCA was suggested, and malignant transformation to hepatocellular carcinoma (HCC) was shown to be strongly associated with activating mutations in β-catenin. Here, we report three cases of HCA in Korean patients: 7-cm, inflammatory and β-catenin-activated HCA with HCC transformation in a 46-year-old man; 13-cm, β-catenin-activated HCA with cytological atypia in a 23-year-old woman; and 10-cm, pigmented, inflammatory and β-catenin-activated HCA in a 36-year-old man. All cases exhibited the nuclear expression of β-catenin and diffuse cytoplasmic expression of glutamine synthetase upon immunohistochemical staining. All tumors were completely resected, and the patients were followed for 3 to 6 years with no evidence of local recurrence or metastasis.ope

Transarterial Therapies for Hepatocellular Carcinoma

BACKGROUND: The treatment of hepatocellular carcinoma (HCC) is still a major health issue because of its increasing incidence and because of the complexity of its management. Transarterial embolization (TAE) and transarterial chemoembolization (TACE) are two widely used locoregional therapies in the treatment of HCC, especially for unresectable intermediate and advanced HCCs. SUMMARY: The modern use of TAE and TACE opens new scenarios for the treatment of unresectable HCC and has yielded interesting results. The present work describes the role of transarterial therapies for HCC and focuses on the different Western and Eastern approaches to the study of response predictors. KEY MESSAGES: Recent refinements in interventional radiology techniques and in HCC patient selection have facilitated better local control of the disease. The molecular profiling of HCC to predict the response to TACE and TAE will greatly help clinicians identify the optimum therapy.ope

IMP2/IGF2BP2 expression, but not IMP1 and IMP3, predicts poor outcome in patients and high tumor growth rate in xenograft models of gallbladder cancer

Overexpression of the oncofetal insulin-like growth factor 2 mRNA-binding protein 2 (IMP2/IGF2BP2) has been described in different cancer types. Gallbladder carcinoma (GBC) is a rare but highly aggressive cancer entity with late clinical detection and poor prognosis. The aim of this study was to investigate the role of IMP2 in human GBC. Tissue microarrays (TMAs) of an international multi-center GBC sample collection from n = 483 patients were analyzed by immunohistochemistry. IMP2 immunoreactivity was found in 74.3% of the tumor samples on TMA, of which 14.0% showed strong and 86.0% low staining intensity. 72.4% of the tumor samples were IMP1 positive, but IMP1 showed lower expression in tumor tissue compared to control tissues. IMP3 immunoreactivity was observed in 92.7% of all tumors, of which 53.6% revealed strong IMP3 expression. Kaplan-Meier analysis linked high IMP2 expression to shorter survival time (p = 0.033), whereas neither IMP1 nor IMP3 expression was linked to a decreased survival time. Eight different human biliary tract cancer (BTC) cell lines were evaluated for tumor growth kinetics in mouse xenografts. Cell lines with high IMP2 expression levels showed the fastest increase in tumor volumes in murine xenografts. Furthermore, IMP2 expression in these cells correlated with the generation of reactive oxygen species (ROS) and RAC1 expression in BTC cells, suggesting RAC1-induced ROS generation as a potential mechanism of IMP2-promoted progression of GBC. In conclusion, IMP2 is frequently overexpressed in GBC and significantly associated with poor prognosis and growth rates in vivo. IMP2 might therefore represent a new target for the treatment of advanced GBC.ope

Intramuscular Neural Arborization of the Latissimus Dorsi Muscle: Application of Botulinum Neurotoxin Injection in Flap Reconstruction

Postoperative pain after breast reconstruction surgery with the latissimus dorsi flap is a common occurrence. Botulinum neurotoxin (BoNT) injection during surgery is effective in reducing postoperative pain. This study aimed to determine the most appropriate locations for BoNT injection. A modified Sihler's method was performed on the latissimus dorsi muscles in 16 specimens. Intramuscular nerve arborization was noted under the landmark of the medial side surgical neck of the humerus to the line crossing the spinous process of T5 and the middle of the iliac crest. The latissimus dorsi muscles were divided into medial, middle, and lateral segments with 10 transverse divisions to give 10 sections (each 10%). Intramuscular nerve arborization of the latissimus dorsi muscle was the largest from the medial and lateral part of the muscle ranging from 40 to 60%, middle part from 30 to 60% and medial, middle and lateral part from 70 to 90%. The nerve entry points were at the medial and lateral part with 20-40% regarding the medial side of surgical neck of the humerus to the line crossing spinous process of T5 to the middle of iliac crest. These outcomes propose that an injection of BoNT into the latissimus dorsi muscles should be administered into specific zones.ope

Whole-Genome and Epigenomic Landscapes of Etiologically Distinct Subtypes of Cholangiocarcinoma

Cholangiocarcinoma (CCA) is a hepatobiliary malignancy exhibiting high incidence in countries with endemic liver-fluke infection. We analyzed 489 CCAs from 10 countries, combining whole-genome (71 cases), targeted/exome, copy-number, gene expression, and DNA methylation information. Integrative clustering defined 4 CCA clusters-fluke-positive CCAs (clusters 1/2) are enriched in ERBB2 amplifications and TP53 mutations; conversely, fluke-negative CCAs (clusters 3/4) exhibit high copy-number alterations and PD-1/PD-L2 expression, or epigenetic mutations (IDH1/2, BAP1) and FGFR/PRKA-related gene rearrangements. Whole-genome analysis highlighted FGFR2 3' untranslated region deletion as a mechanism of FGFR2 upregulation. Integration of noncoding promoter mutations with protein-DNA binding profiles demonstrates pervasive modulation of H3K27me3-associated sites in CCA. Clusters 1 and 4 exhibit distinct DNA hypermethylation patterns targeting either CpG islands or shores-mutation signature and subclonality analysis suggests that these reflect different mutational pathways. Our results exemplify how genetics, epigenetics, and environmental carcinogens can interplay across different geographies to generate distinct molecular subtypes of cancer.Significance: Integrated whole-genome and epigenomic analysis of CCA on an international scale identifies new CCA driver genes, noncoding promoter mutations, and structural variants. CCA molecular landscapes differ radically by etiology, underscoring how distinct cancer subtypes in the same organ may arise through different extrinsic and intrinsic carcinogenic processes.ope

YAP inactivation in estrogen receptor alpha-positive hepatocellular carcinoma with less aggressive behavior

The expression of estrogen receptor alpha (ERα, encoded by ESR1) has been shown to be associated with the prognostic outcomes of patients in various cancers; however, its prognostic and mechanistic significance in hepatocellular carcinoma (HCC) remain unclear. Here, we evaluated the expression of ERα and its association with clinicopathological features in 339 HCC patients. ERα was expressed in 9.4% (32/339) of HCCs and was related to better overall survival (OS; hazard ratio [HR] = 0.11, p = 0.009, 95% C.I. = 0.016-0.82) and disease-free survival (DFS, HR = 0.4, p = 0.013, 95% C.I. = 0.18-0.85). ERα expression was also associated with features related to more favorable prognosis, such as older age, lower serum alpha-fetoprotein level, and less microvascular invasion (p < 0.05). In addition, to obtain mechanistic insights into the role of ERα in HCC progression, we performed integrative transcriptome data analyses, which revealed that yes-associated protein (YAP) pathway was significantly suppressed in ESR1-expressing HCCs. By performing cell culture experiments, we validated that ERα expression enhanced YAP phosphorylation, attenuating its nuclear translocation, which in turn suppressed the downstream signaling pathways and cancer cell growth. In conclusion, we suggest that ERα expression is an indicator of more favorable prognosis in HCC and that this effect is mediated by inactivation of YAP signaling. Our results provide new clinical and pathobiological insights into ERα and YAP signaling in HCC.ope

A Comprehensive Review of Hepatocellular Carcinoma Enhancement Patterns in MRI: Emphasis on Gadoxetate-Enhanced Imaging

In patients at high risk of hepatocellular carcinoma (HCC), such as those with chronic hepatitis or cirrhosis, the confirmative diagnosis of HCC can be made solely from characteristic imaging findings on contrast-enhanced CT or MR scans. However, in daily practice, HCCs showing atypical imaging features are frequently encountered. Since the criteria for diagnosis of HCC is based on dynamic contrast enhancement patterns, it is essential to thoroughly understand these patterns. In this article, we aim to use gadoxetate-enhanced MRI to comprehensively review the HCC enhancement patterns and the associated histopathologic findings with their prognostic factors.ope