• Journal of Korean Neurosurgical Society
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• v.67 no.2
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• pp.146-157
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• 2024

Objective : Chronic subdural hematomas (cSDHs) are generally known to result from traumatic tears of bridging veins. However, the causes of repeat spontaneous cSDHs are still unclear. We investigated the changes in vasculature in the human dura mater and outer membrane (OM) of cSDHs to elucidate the cause of their spontaneous repetition. Methods : The dura mater was obtained from a normal control participant and a patient with repeat spontaneous cSDHs. The pathological samples from the patient included the dura mater and OM tightly adhered to the inner dura. The samples were analyzed with a particular focus on blood and lymphatic vessels by immunohistochemistry, 3-dimensional imaging using a transparent tissue clearing technique, and electron microscopy. Results : The dural border cell (DBC) layer of the dura mater and OM were histologically indistinguishable. There were 5.9 times more blood vessels per unit volume of tissue in the DBC layer and OM in the patient than in the normal control. The DBC layer and OM contained pathological sinusoidal capillaries not observed in the normal tissue; these capillaries were connected to the middle meningeal arteries via penetrating arteries. In addition, marked lymphangiogenesis in the periosteal and meningeal layers was observed in the patient with cSDHs. Conclusion : Neovascularization in the OM seemed to originate from the DBC layer; this is a potential cause of repeat spontaneous cSDHs. Embolization of the meningeal arteries to interrupt the blood supply to pathological capillaries via penetrating arteries may be an effective treatment option.

• BMB Reports
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• v.51 no.7
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• pp.315-316
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• 2018

Genome engineering with clustered regularly interspaced short palindromic repeats (CRISPR) system can be used as a tool to correct pathological mutations or modulate gene expression levels associated with pathogenesis of human diseases. Owing to well-established local administration methods including intravitreal and subretinal injection, it is relatively easy to administer therapeutic genome engineering machinery to ocular tissues for treating retinal diseases. In this context, we have investigated the potential of in vivo genome engineering as a therapeutic approach in the form of ribonucleoprotein or CRISPR packaged in viral vectors. Major issues in therapeutic application of genome engineering include specificity and efficacy according to types of CRISPR system. In addition to previous platforms based on ribonucleoprotein and CRISPR-associated protein 9 derived from Campylobacter jejuni, we evaluated the therapeutic effects of a CRISPR RNA-guided endonuclease derived from Lachnospiraceae bacterium ND2006 (LbCpf1) in regulating pathological angiogenesis in an animal model of wet-type age-related macular degeneration. LbCpf1 targeting Vegfa or Hif1a effectively disrupted the expression of genes in ocular tissues, resulting in suppression of choroidal neovascularization. It was also notable that there were no significant off-target effects in vivo.

• YAKHAK HOEJI
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• v.37 no.5
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• pp.532-537
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• 1993

Angiogenesis refers to the formation of new capillary blood vessels, or neovascularization occurring under various physical conditions, such as development of the embryo, formation of corpus luteum, wound healing and pathological conditions including tumor growth and metastases, hemangiomas, diabetic retinopathy, rheumatoid arthritis. There are many evidences that angiogenesis is important for the progressive growth of solid tumors and also permits the shedding of metastatic tumors from the primary site. Thus, treatment of angiogenesis inhibitors might be a novel strategy for tumor growth inhibition. Normal vascular endothelial cells are in a state of differentiation and angiogenic endothelial cells migrate and proliferate, and they subsequently differentiate into vessel-forming quiescent phenotype cells, Therfore, it was speculated that a modifier of cell differentiation could also affect angiogenesis. In order to identify new antiangiogenic factors, the research was conducted to estimate the inhibitory activities of cell differentiation agents by means of chick embryo chorioallantoic membrane(CAM) assay. Hence, we have established the CAM assay for the screening of antiangiogenic agents. Using the CAM assay, we found that ursolic acid, a tumor cell differentiation-inducing agent, showed a markedly inhibitory effect on chick embryonic angiogenesis.

• Journal of Chest Surgery
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• v.39 no.11 s.268
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• pp.828-837
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• 2006

Background: Tissue hypoxia is characteristic of many human malignant neoplasm, and hypoxia inducible factor-1(HIF-1) plays a pivotal role in essential adaptive response to hypoxia, and activates a signal pathway for the expression of the hypoxia-regulated genes, resulting in increasing $O_2$ delivery or facilitating metabolic adaptation to hypoxia. Increased level of HIF-$1{\alpha}$ has been reported in many human malignancies, but in non-small cell lung carcinoma the influence of HIF-$1{\alpha}$ on tumor biology, including neovascularization, is not still defined. In present study the relationship of HIF-$1{\alpha}$ expression on angiogenetic factors, relationship between the tumor proliferation and HIF-$1{\alpha}$ expression, interaction of HIF-$1{\alpha}$ expression and p53, and relationship between HIF-$1{\alpha}$ expression and clinico-pathological prognostic parameters were investigated. Material and Method: Archival tissue blocks recruited in this study were retrieved from fifty-nine patients with primary non-small cell lung carcinoma, who underwent pneumonectomy or lobectomy from 1997 to 1999. HIF-$1{\alpha}$, VEGF(vascular endothelial growth factor), and p53 protein expression and Ki-67 labeling index in tumor tissues were evaluated, using a standard avidin-biotin-peroxidase complex(ABC) immunohistochemistry. Relationship between the HIF-$1{\alpha}$ expression and VEGF, p53 overexpression and correlation between the HIF-$1{\alpha}$ expresseion and Ki-67 index were analyzed. Clinico-pathologic prognostic parameters were also analyzed. Result: HIF-$1{\alpha}$ expression in cancer cells was found in 24 of 59 cases of non-small cell lung carcinoma(40.7%). High HIF-$1{\alpha}$ expression was significantly associated with several pathological parameters, such as pathological TMN stage(p=0.004), pT stage(p=0.020), pN stage (p=0.029), and lymphovascular invasion(p=0.019). High HIF-$1{\alpha}$ expression was also significantly associated with VEGF immunoreactivity(p<0.001), and aberrant p53 expression(p=0.040). but was marginally associated with Ki-67 labeling index(p=0.092). The overall 5-year survival rate was 42.3%. The survival curve of patients with a high HIF-$1{\alpha}$ expression was worse than that of patients with low-expression(p=0.002). High HIF-$1{\alpha}$ expression was independent unfavorable factors with a marginal significance in multivariate analysis performed by Cox regression. Conclusion: It is suggested that high HIF-$1{\alpha}$ expression may be associated with intratumoral neovascularization possibly through HIF-VEGF pathway, and high HIF-$1{\alpha}$ expression could be associated with lymph node metastasis and post operative poor prognosis in patients with non-small cell lung carcinoma.

• Archives of Plastic Surgery
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• v.43 no.6
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• pp.491-497
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• 2016

Background Hypertrophic scarring is a pathological condition that occurs after trauma or surgery. Angiogenesis occurs more often with hypertrophic scarring than with normotrophic scarring. The regulation of angiogenesis is one of the key factors in hypertrophic scar management. Vascular endothelial growth factor (VEGF) is an essential factor in the angiogenetic response. This study investigated whether decreasing the level of VEGF is effective for treating hypertrophic scarring. Methods Ten 8-week-old female New Zealand white rabbits were included. Four defects were created on each ear by using a 6-mm punch. Bevacizumab (Avastin, Roche Pharma, Basel, Switzerland) was administered in one ear and normal saline was administered in the other ear. Treatment was administered starting on day 2, every 2 days, until day 14. The levels of VEGF were measured using enzyme-linked immunosorbent assay on day 10 and histologic results were analyzed on day 40. Results Bevacizumab induced-defects showed less hypertrophic scarring when compared with the control group as measured by the scar elevation index (SEI) and loose collagen arrangement. The SEI in the experimental group was $1.89{\pm}0.13$, compared to $1.99{\pm}0.13$ in the control group (n=30, P=0.005). Additionally, the VEGF level was lower ($38.72{\pm}11.03pg$ vs. $82.50{\pm}21.64pg$, n=10, P=0.001) and fewer vessels existed ($8.58{\pm}0.76$ vs. $7.2{\pm}1.20$, n=10, P=0.007). Conclusions Preventing excessive angiogenesis is effective for preventing scar formation, especially with hypertrophic scarring. Although it is not an approach that is sufficient alone for the management of scarring, it may be one of several important strategies for scar treatment.

• Journal of Korean Neurosurgical Society
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• v.29 no.10
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• pp.1303-1308
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• 2000

Objectives : It has been known that vascular endothelial growth factor(VEGF), as an endothelial cell-specific mitogen, induces angiogenesis, and possesses vascular permeability and procoagulant properties. Peritumoral brain edema(PTBE) is a common accompaniment of malignant gliomas. It results from microvascular extravasation of plasma and proteins through the interendothelial spaces. The correlation between pathological grading, PTBE, neovascularization, and the expression of VEGF were analyzed in 31 patients with astrocytic tumors. Methods : Astrocytic tumor samples(8 astrocytomas, 14 anaplastic astrocytomas, and 9 glioblastomas) from 31 patients( 21 males and 10 females : average age $37{\pm}24$ years) who underwent surgery were examined retrospectively for the expression of VEGF and CD31(microvasculature) immunohistochemically. The extent of PTBE was examined by using preoperative CT or MRI as an edema index(EI). In addition to VEGF and CD31, several causative factors including tumor size, histologic type were compared with EI. Results : Only one of 8 astrocytomas, and majority of high grade(21 of 23 anaplastic astrocytomas and glioblastomas) tumors demonstrated PTBE(p<0.05). The majority of high grade tumors showed higher expression of VEGF (p<0.01). High grade tumors showed even higher CD31 expression(p<0.05), however, there was no close correlation between expression of VEGF and CD31. The EI was increased significantly, just as VEGF(p<0.01), but CD31 expression was not correlated with high EI. Conclusion : These data suggest that VEGF expression is closely correlated with PTBE and histological grading in astrocytic tumors. Microvasculature(CD31) in tumors is highly correlated with histological grading, however, shows no correlation with the expression of VEGF and PTBE.

• Journal of Chest Surgery
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• v.37 no.8
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• pp.691-701
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• 2004

Background: Tissue hypoxia is a characteristic of many human malignant neoplasms, and hypoxia inducible factor-1 (HIF-1) plays a pivotal role in essential adaptive response to hypoxia, and activates a signal pathway for the expression of the hypoxia-regulated genes, resulting in increased oxygen delivery or facilitating metabolic adaptation to hypoxia. Increased level of HIF-1 a has been reported in many human malignancies, but in esophageal squamous cell carcinoma, the influence of HIF-1 a on tumor biology, including neovascularization, is not still defined. Material and Method: The influence of HIF-1 a expression on angiogenic factors, correlation between the tumor proliferation and HIF-1 a expression, interaction of HIF-1 a expression and p53, and correlation between HIF-1 a expression and clinicopathological prognostic parameters were investigated, using immunohistochemical stains for HIF-1 a, VEGF, CD34, p53, and Ki-67 on 77 cases of resected esophageal squamous cell carcinoma. Result: HIF-1 a expression in cancer cells was found in 33 of 77 esophageal squamous cell carcinoma cases. The 33 cases (42.9%) showed positive stain for HIF-1 a. High HIF-1 a expression was significantly associated with several pathological parameters, such as histologic grade (p=0.032), pathological TMN stage (p=0.002), the depth of tumor invasion (p=0.022), regional lymph node metastasis (p=0.002), distant metastasis (p=0.049), and lymphatic invasion (p=0.004). High HIF-1 a expression had significant VEGF immunoreactivity (p=0.008) and Ki-67 labeling index (p<0.001), but was not correlated with microvascular density within tumors (p=0.088). The high HIF-1 a expression was correlated with aberrant p53 accumulation with a marginal significance (p=0.056). The overall 5-year survival rate was 34.9%. The survival rate of patients with a high HIF-1 a expression was worse than that of patients with low-expression tumors (log-rank test, p=0.0001). High HIF-1 a expression was independent unfavorable factors although statistical significance is marginal in multivariate analysis. Conclusion: It is suggested that (1) high HIF-1 a expression in esophageal squamous cell carcinoma is associated with tumor hypoxia, or with genetic alteration in early carcinogenesis and progressive stages, (2) high HIF-1 a expression may be associated with intratumoral neovascularization through HIF-VEGF pathway, and (3) high HIF-1 a expression is associated with poor prognosis in patients with esophageal squamous cell carcinoma and may playa role as biomarker for regional lymph node metastasis.

• Journal of Periodontal and Implant Science
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• v.33 no.1
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• pp.91-102
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• 2003

Several effective treatment methods and materials have been developed for the treatment of furcation involvement. Currently, the combination of guided tissue regeneration (GTR) and bone grafts is the most commonly prescribed method of treating furcation involved defects. But because these cases often present with poor accessibility, placement of the membrane may be difficult and consequently, clinically impractical. In this study, the alveolar bone healing patterns of adult beagle dogs presenting with alveolar bone destruction treated by one of two methods - treatment using solely bone allografts (BBP(R)), or treatment using bone allografts (BBP(R)) stabilized by a fibrin adhesive - were comp ared. The effects of the fibrin adhesive on the initial stabilization of the newly formed bone, subsequent regeneration of bone, and the feasibility of the clinical application of the fibrin adhesive were analyzed. The results of the study were as follows: 1. Clinical signs of inflammation at the 4-8 week interval were not observed: but signs of mild inflammation were histologically observed at the 4-week interval. 2. Allografts stabilized by fibrin adhesive showed good bone formation, whereas defects treated with only the allograft material showed incomplete alveolar bone regeneration. 3. Allografts stabilized by fibrin adhesive showed a decrease in the amount old bone with a concurrent increase in the formation of new lamellar bone four weeks post-op, whereas defects treated with only the allograft material showed no new lamellar bone formation at the same interval. 4. In detects treated with only the allograft material, the defective area was filled with connective tissue 8-weeks post-op, whereas fibrin adhesive stabilized allografts showed viable connections between the original bone and the newly formed bone, in addition to neovascularization 8-weeks post-op. The results of this study show that concurrent use of fibrin adhesive materials can stabilize the allograft material and aid in new bone formation Although the stability of fibrin adhesives fall short of the results achievable by GTR membranes, in cases presenting with poor accessibility that contraindicate the use of membranes, fibrin adhesive materials provide a viable and effective alternative to graft stabilization and new bone formation.