• Title/Summary/Keyword: histological study

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The Changes of Cerebral Metabolic and Hemodynamic Parameters, Brain Histology, and Serum Levels of Neuron-Specific Enolase During Retrograde Cerebral Perfusion Under Pofound Hypothermic total Circulatory Arrest in Pigs (돼지에서 초저체온 순환정지 하의 역행성 뇌관류시 뇌대사, 혈류역학 지표, 뇌조직 소견 및 혈청 내 neuron-specific enolase의 변화)

  • Kim, Kyung-Hwan;Ahn, Hyuk
    • Journal of Chest Surgery
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    • v.33 no.6
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    • pp.445-468
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    • 2000
  • Background: Retrograde cerebral perfusion(RCP) is currently used for brain protection during aorta surgery, however, for the safety of it, various data published so far are insufficient. We performed RCP using pig and investiaged various parameters of cerebral metabolism and brain injury after RCP under deep hypothermia. Material and Method: We used two experimental groups: in group I(7 pigs, 20 kg), we performed RCP for 120 minutes and in group II (5 pigs, 20 kg), we did it for 90 minutes. Nasopharyngeal temperature, jugular venous oxygen saturation, electroencephalogram were continuously monitored, and we checked the parameters of cerebral metabolism, histological changes and serum levels of neuron-specific enolose(NSE) and lactic dehydrogenase(LDH). Central venous pressure during RCP was mainained in the range of 25 to 30 mmHg. Result: Perfusion flow rates(ml/min) during RCP were 130$\pm$57.7(30 minutes), 108.6$\pm$55.2(60 minutes), 107.1$\pm$58.8(90 minutes), 98.6$\pm$58.7(120 minutes) in group I and 72$\pm$11.0(30 minutes), 72$\pm$11.0(60 minutes), 74$\pm$11.4(90 minutes) in group II. The ratios of drain flow to perfusion flow were 0.18(30 minutes), 0.19(60 minutes), 0.17(90 minutes), 0.16(120 minutes) in group I and 0.21, 0.20, 0.17 in group II. Oxygen consumptions(ml/min) during RCP were 1.80$\pm$1.37(30 minutes), 1.72$\pm$1.23(60 minutes), 1.38$\pm$0.82(90 minutes), 1.18$\pm$0.67(120 minutes) in group I and 1.56$\pm$0.28(30 minutes), 1.25$\pm$0.28(60 minutes), 1.13$\pm$0.26(90 minutes). We could observe an decreasing tendency of oxygen consumption after 90 minutes of RCP in group I. Cerebrovascular resistance(dynes.sec.cm-5) during RCP in group I incrased from 71370.9$\pm$369145.5 to 83920.9$\pm$49949.0 after the time frame of 90 minutes(p<0.05). Lactate(mg/min) appeared after 30 minutes of RCP and the levels were 0.15$\pm$0.07(30 minutes), 0.18$\pm$0.10(60 minutes), 0.19$\pm$0.19(90 minutes), 0.18$\pm$0.10(120 minutes) in group I and 0.13$\pm$0.09(30 minutes), 0.19$\pm$0.03(60 minutes), 0.29$\pm$0.11(90 minutes) in group II. Glucose utilization, exudation of carbon dioxide, differences of cerebral tissue acidosis between perfusion blood and drain blood were maintained constantly during RCP. Oxygen saturation levels(%) in drain blood during RCP were 22.9$\pm$4.4(30 minutes), 19.2$\pm$4.5(60 minutes), 17.7$\pm$2.8(90 minutes), 14.9$\pm$2.8(120 minutes) in group I and 21.3$\pm$8.6(30 minutes), 20.8$\pm$17.6(60 minutes), 21.1$\pm$12.1(90 minutes) in group II. There were no significant changes in cerebral metabolic parameters between two groups. Differences in serum levels of NSE and LDH between perfusion blood and drain blood during RCP showed no statistical significance. Serum levels of NSE and LDH after resuming of cardipulmonary bypass decreased to the level before RCP. Brain water contents were 0.73$\pm$0.03 in group I and 0.69$\pm$0.06 in group II and were higher than those of the controls(p<0.05). The light microscopic findings of cerebral neocortex, basal ganglia, hippocampus(CA1 region) and cerebellum showed no evidence of cerebral injury in two groups and there were no different electron microscopy in both groups(neocortex, basal ganglia and hippocampus), but they were thought to be reversible findings. Conclusion: Although we did not proceed this study after survival of pigs, we could perform the RCP successfully for 120 minutes with minimal cerebral metabolism and no evidence of irreversible brain damage. The results of NSE and LDH during and after RCP should be reevaluated with survival data.

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Histological Comparison of Vascular Grafts in a Pig to Goat Xenotransplantation Model (돼지-염소 이종이식모델에서 냉동 및 무세포화 혈관이식편의 조직학적 비교분석)

  • Yang Ji-Hyuk;Sung Ki-Ick;Kim Won-Geon
    • Journal of Chest Surgery
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    • v.39 no.6 s.263
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    • pp.427-433
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    • 2006
  • Background: Current vascular prostheses are considered still inadequate for reconstruction of small-diameter vessels. To evaluate the potential use of xenograft vessels as small diameter arterial grafts, we implanted porcine vessels in goats. The grafts were treated with two different processes, freezing and acellularization, before implantation, and gross inspection as well as microscopic examination followed after a predetermined period. Material and Method: Bilateral porcine carotid arteries were harvested and immediately stored at $-70^{\circ}C$ within tissue preservation solution. One of them was designated as frozen xenograft vessel. The other one was put on acellularization process using NaCl-SDS solution and stored frozen until further use. Grafts were implanted in the place of carotid arteries of the same goat. The grafts have remained implanted for 1, 3, and 6 months in three animals, respectively. Periodic ultrasonographic examinations were performed during the observation period. After explantation, the grafts were analyzed grossly and histologically under light microscope. Result: All animals survived the experimental procedure without problems. Ultrasonographic examinations showed excellent patency of all the grafts during the observation period. Gross examination revealed nonthrombotic, patent lumens with smooth surfaces. Microscopic examinations of the explanted grafts showed cellular reconstruction at the 6-month stage in both grafts. Although more inflammatory responses were observed in the early phase of frozen xenografts, there was no evidence of significant rejection. Conclusion: These findings suggest that porcine xenograft vessels, regardless of pre-implantation processes of acelluarization or freezing, can be acceptably implanted in goats, although short duration of observation in a small number of animals may limit this study.

Diagnosis of Malignant Pleural Effusion by using Aberrant Methylation of p16 and RARB2 (p16과 RARB2 유전자의 비정상적인 메틸화 검사를 이용한 악성 흉수의 진단)

  • Rha, Seo Hee;Lee, Su Mi;Koo, Tae Hyoung;Shin,, Bong Chul;Huh, Jung Hun;Um, Soo Jung;Yang, Doo Kyung;Lee, Soo-Keol;Son, Choonhee;Roh, Mee Sook;Bae, Ho-Jeong;Kim, Ki Nam;Lee, Ki Nam;Choi, Pil Jo
    • Tuberculosis and Respiratory Diseases
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    • v.64 no.4
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    • pp.285-292
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    • 2008
  • Background: A diagnosis of malignant pleural effusion is clinically important, as the prognosis of lung cancer patients with malignant pleural effusion is poor. The diagnosis will be difficult if a cytological test is negative. This study was performed to investigate whether the detection of hypermethylation of the p16 (CDKN2A) and retinoic acid receptor b2 (RARB2) genes in pleural fluid is useful for a diagnosis of malignant pleural effusion. Methods: Pleural effusion was collected from 43 patients and was investigated for the aberrant promoter methylation of the RARB2 and CDKN2A genes by use of methylation-specific PCR. Results were compared with findings from a pleural biopsy and from pleural fluid cytology. Results: Of 43 cases, 17 cases of pleural effusion were due to benign diseases, and 26 cases were from lung cancer patients with malignant pleural effusion. Hypermethylation of the RARB2 and CDKN2A genes was not detected in the case of benign diseases, independent of whether or not the patients had ever smoked. In 26 cases of malignant pleural effusion, hypermethylation of RARB2, CDKN2A or either of these genes was detected in 14, 5 and 15 cases, respectively. The sensitivities of a pleural biopsy, pleural fluid cytology, hypermethylation of RARB2, hypermethylation of CDKN2A, or hypermethylation of either of the genes were 73.1%, 53.8%, 53.8%, 19.2%, and 57.7%, respectively; negative predictive values were 70.8%, 58.6%, 58.6%, 44.7%, and 60.7%, respectively. If both genes are considered together, the sensitivity and negative predictive value was lower than that for a pleural biopsy, but higher than that for pleural fluid cytology. The sensitivity of hypermethylation of the RARB2 gene for malignant pleural effusion was lower in small cell lung cancers than in non-small cell lung cancers. Conclusion: These results demonstrate that detection of hypermethylation of the RARB2 and CDKN2A genes showed a high specificity, and sensitivity was higher than for pleural fluid cytology. With a better understanding of the pathogenesis of lung cancer according to histological types at the molecular level, and if appropriate genes are selected for hypermethylation testing, more precise results may be obtained.

Effects Of Cultured Bone Cell On The Regeneration Of Alveolar Bone (배양골세포 이식이 치조골재생에 미치는 영향)

  • Jeong, Soon-Joon;Herr, Yeek;Park, Joon-Bong;Lee, Man-Sup;Kwon, Young-Hyuk
    • Journal of Periodontal and Implant Science
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    • v.26 no.1
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    • pp.1-26
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    • 1996
  • This study was performed to estimate the effects of cultured bone cell inoculated on porous type hydroxyaptite for the regeneration of the artificial alveolar bone defect. In this experiment 3 beagle dogs were used, and each of them were divided into right and left mandible. Every surgical intervention were performed under the general anesthesia by using with intravenous injection of Pentobarbital sodium(30mg/Kg). To reduce the gingival bleeding during surgery, operative site was injected with Lidocaine hydrochloride(l:80,000 Epinephrine) as local anesthesia. After surgery experimental animal were feeded with soft dietl Mighty dog, Frisies Co., U.S.A.) for 1 weeks to avoid irritaion to soft tissue by food. 2 months before surgery both side of mandibular 1st premolar were extracted and bone chips from mandibular body were obtained from all animals. Bone cells were cultured from bone chips obtained from mandible with Dulbecco's Modified Essential Medium contained with 10% Fetal Bovine Serum under the conventional conditions. Porous type hydroxyapatite were immerse into the high concentrated cell suspension solution, and put 4 hours for attachin the cells on the surface of hydroxyapatite. Graft material were inserted on the artificial bone defect after 3 days of culture. Before insertion of cellinoculated graft material, scanning electronic microscopic observation were performed to confirm the attachment and spreading of cell on the hydroxyapatite surface. 3 artificial bone defects were made with bone trephine drill on the both side of mandible of the experimental animal. First defect was designed without insertion of graft material as negative control, second was filled with porous replamineform hydroxyapatite inoculated with cultured bone marrow cells as expermiental site, and third was filled with graft materials only as positive control. The size of every artificial bone defect was 3mm in diameter and 3mm in depth. After the every surgical intervention of animals, oral hygiene program were performed with 1.0% chlorhexidine digluconate. All of the animals were sacrificed at 2, 4, 6 weeks after surgery. For obtaining histological section, tissus were fixed in 10% Buffered formalin and decalcified with Planko - Rycho Solution for 72hr. Tissue embeding was performed in paraffin and cut parallel to the surface of mandibular body. Section in 8um thickness of tissue was done and stained with Hematoxylin - Eosin. All the specimens were observed under the light microscopy. The following results were obtained : 1. In the case of control site which has no graft material, less inflammatory cell infiltration and rapid new bone forming tendency were revealed compared with experimental groups. But bone surface were observed depression pattern on defect area because of soft tissue invasion into the artificial bone defect during the experimental period. 2. In the porous hydroxyapatite only group, inflammatory cell infiltration was prominet and dense connective tissue were encapsulated around grafted materials. osteoblastic activity in the early stage after surgery was low to compared with grafted with bone cells. 3. In the case of porous hydroxyapatite inoculated with bone cell, less inflammatory cell infiltration and rapid new bone formation activity was revealed than hydroxyapatite only group. Active new bone formation were observed in the early stage of control group. 4. The origin of new bone forming was revealed not from the center of defected area but from the surface of preexisting bony wall on every specimen. 5. In this experiment, osteoclastic cell was not found around grafted materials, and fibrovascular invasion into regions with no noticeable foreign body reaction. Conclusively, the cultured bone cell inoculated onto the porous hydroxyapatite may have an important role of regeneration of artificial bone defects of alveolar bone.

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Inhibitory Activities of Water Extracts of Black Ginseng on HCl/Ethanol-Induced Acute Gastritis through Anti-Oxidant Effect (흑삼 열수 추출물의 항산화 효과를 통한 염산/에탄올로 유발된 위염 억제 작용)

  • Kim, Min Yeong;Kwon, O Jun;Noh, Jeong Sook;Roh, Seong-Soo
    • Journal of the Korean Society of Food Science and Nutrition
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    • v.45 no.9
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    • pp.1249-1256
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    • 2016
  • Black ginseng (BG) obtained by a 9-fold steaming process of Panax ginseng has been reported to have anti-oxidative, anti-obesity, and anti-diabetes effects. The current study evaluated the protective effect of BG by steaming time in an HCl/ethanol-induced acute gastritis model. BG was divided into four samples according to steaming-drying processing (Gin1, Gin3, Gin6, and BG). High performance liquid chromatography analysis, free radical scavenging activity, and total phenol and flavonoid contents were examined in ginseng and four BG samples. Compared with ginseng, BG showed a stronger radical scavenging effect and higher contents of total phenol and flavonoids. To evaluate the anti-gastritic effect of BG, mice were distributed into five groups: normal mice (N), acute gastritic mice with distilled water (CON), acute gastritic mice with 100 mg/kg of ginseng (Gin0), acute gastritic mice with 100 mg/kg of BG (BG), and acute gastritic mice with 10 mg/kg of sucralfate (SC). After 1 hour of pre-treatment with water, extracts (Gin0 and BG), or drug (SC), experimental groups except for N were orally administered 0.5 mL of 150 mM HCl/60% ethanol (v/v) mixture. Blood was collected 1 hour later from the heart, and gastric tissue was harvested. Reactive oxygen species (ROS) levels were measured in serum, and related protein expression was examined by Western blot assay. In HCl/ethanol-induced acute gastritic mice, treatment with ginseng or BG improved mucosal damage in the histological evaluation. The serum ROS level significantly decreased in the BG-treated group compared with the CON group. Furthermore, expression of inflammatory cytokines significantly decreased in the BG-treated group compared with the CON group. Based on these results, antioxidant and anti-gastritic activities of ginseng were enhanced by streaming-drying processing, in part due to an increase in biological active compounds.

The Anti-inflammatory Effect of Skipjack Tuna (Katsuwonus pelamis) Oil in LPS-induced RAW 264.7 Cells and Mouse Models (LPS 유도 RAW 264.7 세포와 마우스 모델에서 참치(Katsuwonus pelamis) 유의 항염증 효과)

  • Kang, Bo-Kyeong;Kim, Min-Ji;Kim, Koth-Bong-Woo-Ri;Ahn, Na-Kyung;Choi, Yeon-Uk;Bark, Si-Woo;Pak, Won-Min;Kim, Bo-Ram;Park, Ji-Hye;Bae, Nan-Young;Ahn, Dong-Hyun
    • Microbiology and Biotechnology Letters
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    • v.43 no.1
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    • pp.45-55
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    • 2015
  • This study was carried out to demonstrate the anti-inflammatory effect of tuna oil (TO) using LPS-induced inflammation responses and mouse models. First, nitric oxide (NO) and pro-inflammatory cytokines levels were suppressed up to 50% with increasing concentrations of TO without causing any cytotoxicity. Also, the expression of a variety of proteins, such as inducible nitric oxide synthase (iNOS), cyclooxygenase-2 (COX-2) and nuclear factor kappa B (NF-κB), was suppressed in a dosedependent manner by treatment with TO. Furthermore, TO also inhibited the phosphorylation of mitogen-activated protein kinases (MAPKs), including c-Jun N-terminal kinase (JNK), extracellular signal-regulated kinase (ERK), and p38 protein kinase (p38). Moreover, in in vivo testing the formation of ear edema was reduced at the highest dose tested compared to that in the control, and a reduction of ear thickness and the number of mast cells was observed in histological analysis. In acute toxicity test, no mortalities occurred in mice administrated 5,000 mg/kg body weight of TO over a two-week observation period. Our results suggest that TO has a considerable anti-inflammatory property through the suppression of inflammatory mediator productions and that it could prove to be useful as a potential anti-inflammatory therapeutic material.

The Effect of Angiotensin Converting Enzyme Inhibitor on Chronic Cyclosporine Nephropathy in Salt Depleted Rats (저염식이를 이용한 cyclosporine 신독성에서 angiotensin converting enzyme Inhibitor의 영향)

  • Lee Eun-Ju;Lee Eun-Sil;Hah Jung-Hi;Kim Yong-Jin;Park Yong-Hoon
    • Childhood Kidney Diseases
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    • v.4 no.2
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    • pp.127-135
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    • 2000
  • Purpose: Cyclosporine(CsA) is a potent immunosuppressant but the use of CsA is associated with various side effects, especially nephrotoxicity. In tile kidney, salt depletion activates tile renin-angiotensin-aldosteron(RAS) system and accentuates chronic CsA nephropathy. We postulate that angiotensin converting enzyme inhibitors(ACEI) can prevent chronic CsA nephropathy, since ACEI may inhibit this cascades. This study was aimed to assess the effect of ACEI on chronic cyclosporin nephropathy in salt depleted rats. Methods: 36 Fischer-344 rats were divided into 6 goups. Group I received normal salt diet(NSD). Group II received a low salt diet(LSD). Group III received CsA with a NSD. Group IV received CsA with a LSD. Group V received NSD+CsA with ACEI. Group VI received LSD+CsA with ACEI. Rats were sacrificed after six weeks and the glomerular filtration rate(GFR), serum sodium, potassium and whole blood cyclosporine levels were measured. Renal tissues me sampled for the observation of histological changes. Results: No differences in blood CsA level & serum sodium were found between groups during the course of this experiment. Serum potassium in group VI was significantly increased compared with group IV and V (P<0.05). In groups treated with CsA only and in those where CsA was combined with ACEI, GFR was found to be significantly more decreased in LSD than NSD, and GFR in group V was significantly decreased in comparison with group III (P<0.05). Renal histologic lesions associated with CsA which consisted of cortical interstitial fibrosis, tubular atrophy and hyalinization of arterioles were more severe in tile LSD group. But, no differences were observed between tile groups treated with CsA and ACEI, and the groups treated with only CsA. Conclusion: Salt depletion associated with the activation of the RAS system accentuated chronic CsA nephrotoxicity, but, ACEI could not reduce the functional and morphological changes of salt depleted kidneys, in which nephropathy can be exacerbated in spite of the blocking of the angiotensin II pathway. further studies are required to elucidate whether Am ameliorated the effect of salt-depleted CsA nephrotoxicity upon the effective renal blood flow.

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Effectiveness of Esophageal Ultrasonography Surgical Therapy of Esophageal Cancer (식도암 수술에서 식도내시경초음파(EUS) 진단의 효용성)

  • Jung, Jae-Seung;Lee, Sung-Ho;Cho, Seong-Joon;Son, Ho-Sung;Sun, Kyung;Kim, Kwang-Taik;Kim, Hyoung-Mook
    • Journal of Chest Surgery
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    • v.36 no.2
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    • pp.91-97
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    • 2003
  • With the advent of stage-adapted multimodal regiments for esophageal malignancy, accurate staging has become of utmost importance. Endoscopic ultrasono graphy(EUS) i.: a diagnostic method for the local staging of esophageal cancer, in particular for T and N evaluation. The aim of this study was to examine the diagnostic efficacy of the EUS and to evaluate the relation between prognosis and EUS findings. Material and Method : We reexamined the cases of 88 consecuitive patients who underwent transthroacic esophagectomy and cervical esophagogastrostomy for esophageal cancer from January 1991 to July 2001 We compared EUS findings, histological results and outcomes. Result : There were 83 male(94.3%) and 5 female. Median age was 61.3 years old. Overall staging accuracy were 59.0% for T staging and 76.0% for N staging, In early T staging group, the accuracy was 74.9% except 74 stage. However significant differences were not found in the ability of EUS-determined T-stage and N-Stage to predict survival. Multivariate analysis showed EUS-stage to predict survival. Conclusion : EUS provides a high degree of accuracy in assessing both T and N parameters in staging esophagal cancer. EUS should be performed in all patients with esophageal cancer, not only for staging before therapy, but also as a valuable method of determining prognosis.

Tissue Distribution of HuR Protein in Crohn's Disease and IBD Experimental Model (염증성 장질환 모델 및 크론병 환자에서의 점막상피 HuR 단백질의 변화 분석)

  • Choi, Hye Jin;Park, Jae-Hong;Park, Jiyeon;Kim, Juil;Park, Seong-Hwan;Oh, Chang Gyu;Do, Kee Hun;Song, Bo Gyoung;Lee, Seung Joon;Moon, Yuseok
    • Journal of Life Science
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    • v.24 no.12
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    • pp.1339-1344
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    • 2014
  • Inflammatory bowel disease is an immune disorder associated with chronic mucosal inflammation and severe ulceration in the gastrointestinal tract. Antibodies against proinflammatory cytokines, including TNF${\alpha}$, are currently used as promising therapeutic agents against the disease. Stabilization of the transcript is a crucial post-transcriptional process in the expression of proinflammatory cytokines. In the present study, we assessed the expression and histological distribution of the HuR protein, an important transcript stabilizer, in tissues from experimental animals and patients with Crohn's disease. The total and cytosolic levels of the HuR protein were enhanced in the intestinal epithelia from dextran sodium sulfate (DSS)-treated mice compared to those in control tissues from normal mice. Moreover, the expression of HuR was very high only in the mucosal and glandular epithelium, and the relative localization of the protein was sequestered in the lower parts of the villus during the DSS insult. The expression of HuR was significantly higher in mucosal lesions than in normal-looking areas. Consistent with the data from the animal model, the expression of HuR was confined to the mucosal and glandular epithelium. These results suggest that HuR may contribute to the post-transcriptional regulation of proinflammatory genes during early mucosal insults. More mechanistic investigations are warranted to determine the potential use of HuR as a predictive biomarker or a promising target against IBD.

Radiation Therapy for Operable Breast Cancer after Conservative Surgery (유방암환자의 유방보존수술 후 방사선 치료 성적)

  • Lee, Myung-Za;Chun, Ha-Chung
    • Radiation Oncology Journal
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    • v.20 no.4
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    • pp.309-315
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    • 2002
  • Purpose : To evaluate the result of conservative management on recurrence, survival and prognostic factors of patient with operable breast cancer. Materials and Methods : Fifty three patients, treated for localized breast cancer by lumpectomy or quadrantectomy followed by radiotherapy between January 1985 and December 1996, were retrospectively studied. All patients followed up for at least five years. Their median age was 43 years $(range\;24\~72)$. The tumor stages were as follows : T1 in 30 patients, T2 in 21, Tis in 2. Thirty-eight patients had negative and 15 had positive axillary nodes. The histological types were 42 infiltrating ductal, 2 infiltrating lobular, and 2 intraductal carcinomas with 7 other histologies. The tumor locations were the outer quadrant in 38 breasts, the inner quadrant in 13 and central in 2. Radiation doses of $46\~50\;Gy$ were given to the entire breast areas with additional doses of 14-18 Gy delivered to the tumor bed areas. Results : The overall five and 10 yea actuarial and disease free survivals were $94.3\%\;and\;92.4\%,\;91.2\%\;and\;81\%$, respectively. The overall five year survivals were $100\%$ in stage I and IIa, and $66.7\%$ in stage IIb and IIIa tumors. Seven patients failed either locally or distantly. Incidence of local failure and distant metastasis for the first failure were $7.5\%\;and\;5.7\%$, respectively. Local recurrence appeared within 2 years of treatment at the primary site and after more than 8 years outside of primary lesion, whereas distant metastasis appeared between 2 and 6 years following treatment. The overall recurrences were high at a young age (< or = 35 years), with 5 out of 12 (2 local, 3 distant), and in T2 lesions with 5 out of 21 (1 local, 3 distant, and 1 in both). Distant metastasis was high in the positive axillary lymph node group with 4 out of 15 $(26.6\%)$. A high incidence in the axillary node was noted at a young age with 7 out of 12 $(58.3\%)$ and in T2 lesions with 8 out of 21 $(38.4\%)$. A young age, positive axillary node and large tumor size were all related with poor survival. Conclusion : Based on this study, lumpectomy or quadrantectomy, followed by radiation appears to be an adequate therapeutic method in operable breast cancer. A long term follow-up is necessary because a recurrence of breast can occur long time after treatment. The poor prognostic group, especially young patients with an aggressive biological behavior needs more effective treatment modalities to improve their survival.