• Molecules and Cells
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• 제38권11호
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• pp.998-1006
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• 2015

Retinols are metabolized into retinoic acids by alcohol dehydrogenase (ADH) and retinaldehyde dehydrogenase (Raldh). However, their roles have yet to be clarified in hepatitis despite enriched retinols in hepatic stellate cells (HSCs). Therefore, we investigated the effects of retinols on Concanavalin A (Con A)-mediated hepatitis. Con A was injected into wild type (WT), Raldh1 knockout ($Raldh1^{-/-}$), $CCL2^{-/-}$ and $CCR2^{-/-}$ mice. For migration study of regulatory T cells (Tregs), we used in vivo and ex vivo adoptive transfer systems. Blockade of retinol metabolism in mice given 4-methylpyrazole, an inhibitor of ADH, and ablated Raldh1 gene manifested increased migration of Tregs, eventually protected against Con A-mediated hepatitis by decreasing interferon-${\gamma}$ in T cells. Moreover, interferon-${\gamma}$ treatment increased the expression of ADH3 and Raldh1, but it suppressed that of CCL2 and IL-6 in HSCs. However, the expression of CCL2 and IL-6 was inversely increased upon the pharmacologic or genetic ablation of ADH3 and Raldh1 in HSCs. Indeed, IL-6 treatment increased CCR2 expression of Tregs. In migration assay, ablated CCR2 in Tregs showed reduced migration to HSCs. In adoptive transfer of Tregs in vivo and ex vivo, Raldh1-deficient mice showed more increased migration of Tregs than WT mice. Furthermore, inhibited retinol metabolism increased survival rate (75%) compared with that of the controls (25%) in Con A-induced hepatitis. These results suggest that blockade of retinol metabolism protects against acute liver injury by increased Treg migration, and it may represent a novel therapeutic strategy to control T cell-mediated acute hepatitis.

• 대한한방내과학회지
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• 제19권1호
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• pp.221-246
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• 1998

The aim of this experimental study was to evaluate the anti-tumor effects of Chungsimbohyeltang through investigation about viability of tumor cell by MTT assay, survival period of mice transplanted with L-1210 cells, growth inhibition on the tumor cell, body weight variation in mice transplanted with sarcoma-180 cells and its immunomodulatory effects through the investigation on delayed type hyper-sensitivity, the hemagglutinin and hemolysin titers for humoral immune response, the appearance of rosette forming cells for cell-mediated immune response, the natural killer cell activity, the transformation of lymphocyte, the productivity of Interleukin-2 and phagocytic index K was performed in immune-depressed ICR mice induced by methotrexate treatments. The results were as follows ; 1. $IC_{50}$ of Chungsimbohyeltang treated group was 5.85mg/ml in SNU-C4 cell, 1.38mg/ml in SNU-396 cell, 0.21mg/ml in SNU-1 cell, so it had low anti-tumor activity. 2. The both groups of Chungsimbohyeltang extract 10mg/kg and Chungsimbohyeltang extract 20mg/kg had no toxicity and the group of Chungsimbohyeltang 20mg/kg which was shown 120% in ILS had the effect of life prolongation in mice transplanted with L-1210 cells. 3. In the growth inhibition on the tumor cells, only the group of Chungsimbohyeltang extract 20mg/kg was noted and in the weight variation in mice transplanted with sarcoma-180 cells, both groups of Chungsimbohyeltang extract had a significant effect. 4. In the delayed type hypersensitivity and appearance of rosette forming cells, both groups of Chungsimbohyeltang extract didn't have any significant effect. 5. The hemagglutinin titers was slightly increased with no significance, and the hemolysin titers was significantly increased in the only group of Chungsimbohyeltang extract 20mg/kg. 6. The natural killer cell activity of the Chungsimbohyeltang extract groups was significantly increased in the ratio of 100:1 of effector and target cells, but it was not significantly increased in the ratio of 50:1, 10:1. 7. The transformation of lymphocyte and the productivity of Interleukin-2 were increased significantly and in dose-dependent manner in both group of Chungsimbohyeltang extract. 8. The phagocytic effect of macropage was significantly increased in both groups of Chungsimbohyeltang extract. Considering the results above, we could conclude that Chungsimbohyeltang have an indirect anti-tumor effect through the modulation of immunme response, although it had not toxicity on the tumor cell it self.

• Journal of Oral Medicine and Pain
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• 제24권2호
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• pp.145-161
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• 1999

The proto-oncogene bcl-2 confers a survival advantage to cells by blocking programmed cell death (apoptosis). Overexpression of bcl-2 probably plays a role in tumorigenesis, and the expression of the bcl-2 protein has been investigated in many kinds of tumors. An increased expression of nitric oxide synthetase(NOS) has been observed in human colon cancer cell lines as well as in human gynecological, breast, and CNS tumors. However there have been only a few reports on the expression of bcl-2 and $NOS_2$ in oral white lesions and cancer. The aim of this study was to investigate the relationship between the expression of Bcl-2 and $NOS_2$ and several pathological parameters such as histological types and layers. We reported desregulation of bcl-2 and $NOS_2$ expression during progression from oral white lesion, lichen planus and leukoplakia to squamous cell carcinoma. The obtained results were as follows: 1. Immunohistochemical analysis with monoclonal antibodies to bcl-2 oncoprotein and $NOS_2$ in formalin-fixed paraffin-embedded tissue sections revealed that bcl-2 expression is restricted to the basal cell layer and $NOS_2$ was mild expressed only in subepithelial inflammatory cells in normal human mucosa. There wasn't specific finding of those in lichen planus and leukoplakia. 2. Bcl-2 immunoreactivity in severe epithelial dysplasia or CIS occurs throughout the epithelium, $NOS_2$ reactivity in most superficial layer were noted. 3. In well-differentiated squamous cell carcinomas, mostly bcl-2 was overexpressed. In moderated and poor squamous cell carcinomas, the expression of $NOS_2$ was increased and that of bcl-2 was decreased. 4. The immunoreactivity of bcl-2 was 12.5% of normal mucosa, 30% of leukoplakia, 44% of lichen planus and 67% of carcinoma in situ. In carcinoma, those were 43%, 50% and 67% according to differentiation, respectively. 5. The immunoreactivity of $NOS_2$ was 25% of normal mucosa, 70% of leukoplakia, 78% of lichen planus and 100% of carcinoma in situ and epithelial dysplasia. In carcinoma, those were higher in moderated(100%) and poor(83%) squamous cell carcinomas than in well differentiated type(71%). 6. The expression of bcl-2 and $NOS_2$ by Western blot was increased highly in lichen planus and leukoplakia. Therefore, the expression of bcl-2 was increased in the white and precancerous lesions and that was decreased by differentiation of carcinoma. However, $NOS_2$ immunoreactivity in carcinoma in situ was lower than those in moderated and poor squamous cell. These findings suggest that the interaction of bcl-2 and $NOS_2$ may be roled importantly in growth and development of carcinoma.

• Tuberculosis and Respiratory Diseases
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• 제85권2호
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• pp.155-164
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• 2022

Background: The remarkable efficacy of osimertinib in non-small cell lung cancer (NSCLC) with acquired T790M mutation has been widely documented in clinical trials and real-world practice. However, some patients show primary resistance to this drug. Even patients who initially show a favorable response have inconsistent clinical outcomes later. Therefore, the aim of this study was to identify additional clinical predictive factors for osimertinib efficacy. Methods: A prospective cohort of patients with acquired T790M positive stage IV lung adenocarcinoma treated with osimertinib salvage therapy in Hallym University Medical Center were analyzed. Results: Sixty-one eligible patients were analyzed, including 38 (62%) women and 39 (64%) who never smoked. Their mean age was 63.3 years. The median follow-up after treatment with epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) was 36.0 months (interquartile range, 24.7-50.2 months). The majority (n=45, 74%) of patients were deceased. Based on univariate analysis, low baseline neutrophil-to-lymphocyte ratios (NLR), age ≥50 years, never-smoking history, stage IVA at osimertinib initiation, and prolonged response to previous TKIs (≥10 months) were associated with a significantly longer progression-free survival (PFS). Multivariate analysis showed that never-smoking status (hazard ratio [HR], 0.54; 95% confidence interval [CI], 0.30-0.98; p=0.041) and a baseline NLR less than or equal to 3.5 (HR, 0.23; 95% CI, 0.12-0.45; p<0.001) were independently associated with a prolonged PFS with osimertinib. Conclusion: Smoking history and high NLR were independent negative predictors of osimertinib PFS in patients with advanced NSCLC developing EGFR T790M resistance after the initial EGFR-TKI treatment.

• Nutrition Research and Practice
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• 제16권3호
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• pp.330-343
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• 2022

BACKGROUND/OBJECTIVES: Zanthoxylum schinifolium is traditionally used as a spice for cooking in East Asian countries. This study was undertaken to evaluate the anti-proliferative potential of ethanol extracts of Z. schinifolium leaves (EEZS) against human bladder cancer T24 cells. MATERIALS/METHODS: Subsequent to measuring the cytotoxicity of EEZS, the anti-cancer activity was measured by assessing apoptosis induction, reactive oxygen species (ROS) generation, and mitochondrial membrane potential (MMP). In addition, we determined the underlying mechanism of EEZS-induced apoptosis through various assays, including Western blot analysis. RESULTS: EEZS treatment concentration-dependently inhibited T24 cell survival, which is associated with apoptosis induction. Exposure to EEZS induced the expression of Fas and Fas-ligand, activated caspases, and subsequently resulted to cleavage of poly (ADP-ribose) polymerase. EEZS also enhanced the expression of cytochrome c in the cytoplasm by suppressing MMP, following increase in the ratio of Bax:Bcl-2 expression and truncation of Bid. However, EEZS-mediated growth inhibition and apoptosis were significantly diminished by a pan-caspase inhibitor. Moreover, EEZS inhibited activation of the phosphoinositide 3-kinase (PI3K)/Akt pathway, and the apoptosis-inducing potential of EEZS was promoted in the presence of PI3K/Akt inhibitor. In addition, EEZS enhanced the production of ROS, whereas N-acetyl cysteine (NAC), a ROS scavenger, markedly suppressed growth inhibition and inactivation of the PI3K/Akt signaling pathway induced by EEZS. Furthermore, NAC significantly attenuated the EEZS-induced apoptosis and reduction of cell viability. CONCLUSIONS: Taken together, our results indicate that exposure to EEZS exhibits anti-cancer activity in T24 bladder cancer cells through ROS-dependent induction of apoptosis and inactivation of the PI3K/Akt signaling pathway.

• Radiation Oncology Journal
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• 제16권3호
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• pp.245-250
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• 1998

목적 : 조기 성문암의 방사선 치료 후 생존율, 실패 양상, 그리고 예후 인자에 대해 분석하였다. 대상 및 방법 : 1985년 6월부터 1992년 11월까지 방사선 치료를 위해 의뢰된 57례의 성문암환자를 대상으로 후향적 분석을 실시하였다. 연령 분포는 17세부터 71세까지 광범위했고 (중앙값 39세), 남자 55례와 여자 2례로 남성에서 호발하였다. 방사선 치료는 6 MV X-ray를 이용하여 1회 선량 2 Gy씩, 주 5회, 총선량 66 Gy를 조사하였다. 결과 : 방사선 치료에 대한 반응은 완전 관해 89.5% (51/57), 부분 관해 혹은 무반응 10.5%(6/57) 였다. 51례의 완전관해 환자 중에서 7례의 재발이 관찰되었고 7례 모두 수술로 구제되었다. 부분 관해 혹은 무반응 6례 중 4례에 대하여 구제수술을 시행하였고 2례에서는 수술을 시행하지 못하였다. 구제수술을 시행한 4례 중 3례가 구제되었고 1례는 다시 국소재발하였다. 3년 및 5년 무병생존율은 각각 72.9% 및 63.8%였다. 병소의 위치에 따른 5년 무병생존율은 후방인 경우 85.5%, 전방인 경우 61.6%였다 (P<0.05). 방사선치료에 대해 부분 관해 혹은 무반응을 보인 5례를 포함하여 13/57 (22.8%) 례의 치료 실패가 관찰되었고 그 중 10/13 (76.9%) 례가 수술로 구제되었다. 최종 5년 국소제어율은 92.3%였고 전체적으로 47/57 (82.5%) 례에서 음성을 보존할 수 있었다. 결론 : 높은 음성 보존율을 고려하면 초기 성문암에서 방사선치료가 우선적으로 고려되어야 한다.

• 한국양식학회지
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• 제8권4호
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• pp.355-366
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• 1995

해산패류양식에서 먹이 생물로서 이용 가능한 7종 규조류(Chaetoceros simplex, Navicula incerta, Phaeodactyiurn tricornutum, Nitzschia closterium, Skeletonema costatum, Thalassiosira pseudonana, Thalassiosira weisspogii)의 먹이 효율을 알아보기 위하여 일간 성장율, 평균 세포 용적, 화학적 성분과 일반 지방산 성분에 관하여 실험하였다. 세포용적을 보면 T pseudonana가 $(125{\mu}m^3)$로서 가장 작았으며 T. weissfogii가 $(824{\mu}m^3)$로서 가장 크게 나타났다. 그러나, 7일간 배양한 7종의 성장율을 살펴보면 S. costatum이 s.g.r.가 0.9928로 가장 높게 나타났고, 세포 용적이 가장 큰 T. weissflogii가 0.5016로서 가장 낮게 나타났다. 조단백질 함량은 T. weissflogii가 $24.4\%$로 가장 높게 나타났고, T. pseudonana, S. costatum이 각각 $19.0\%,\;19.8\%$로 비교적 낮게 나타났다. 조지방 성분 함량은 C. simplex가 $8.4\%$로 가장 높게 나타났으며 다음으로는 N closterium, M incerta, T. weissflogii의 순서였다. 7종 규조류의 주요 지방산 성분은 14:0, 16:0, 16:1 및 18:1이었으며 고도불포화 지방산함량은 비교적 낮게 나타났다. 20:5n-3 (EPA)는 P. tricornutum, C. simplex에 서 각각 $7.73\%,\;5.87\%$의 비율이었으며, 22:6 n-3 (DHA)는 P. tricornutum $0.84\%$, C. simplex $1.75\%$, S. costatum $0.70\%$의 함량을 나타내었다. 참굴 유생의 D상과 초기 각정기 유생에 7종의 규조류를 공급한 먹이효율 결과를 보면, C. simplex 공급구가 성장 및 생존율이 높게 나타났고, S. costatum과 T. weissflogii 공급구가 저조하였다. 이러한 결과를 볼때 C. simplex가 실험에 이용되었던 다른 규조류보다 이매패류의 유생에 더 유용한 먹이생물이 라고 사료된다.

• Journal of Chest Surgery
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• 제39권11호
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• pp.828-837
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• 2006

배경: 악성종양에서 신생혈관 생성 및 당분해의 증가는 저산소 상태의 미세환경을 나타내며, 이는 종양의 침습성, 전이 및 환자의 예후와 관련이 있는 것으로 알려져 있다. Hypoxia-inducible factor 1(HIF-1)는 당원 수송체, 당분해 효소, 혈관내피세포 성장인자 등의 유전자의 전사를 활성화한다고 알려져 있다. 그리고 HIF-1의 전사 활성도는 HIF-$1{\alpha}$ 아단위의 표현이 조절되는 정도에 의존한다. 비소세포 폐암에서 HIF-$1{\alpha}$의 발현이 혈관 생성능, 종양세포 증식능 및 이상형 p53의 축적 등 종양의 생물학적 특성에 미치는 영향과 환자의 수술 후 예후와의 관계를 규명하고자 한다. 대상 및 방법: 1997년부터 1999년까지 비소세포 폐암으로 진단받고 전폐절제술 혹은 폐엽절제술을 시행 받은 59명의 폐암 환자들에서 얻어진 파라핀 조직 블록을 대상으로 하였다. ABC(avidin-biotin complex) 방법에 기초한 면역조직화학검사를 이용하여 암조직과 정상조직에서 HIF-$1{\alpha}$, VEGF(vascular endothelial growth factor), p53 단백의 발현을 조사하고, Ki-67의 발현을 이용한 증식지수를 측정하였다. HIF-$1{\alpha}$ 발현과 환자의 생존기간을 포함한 임상적-병리학적 변수들과의 상관관계, VEGF, p53의 발현과 증식지수와의 상관관계를 분석하였다. 결과: HIF-$1{\alpha}$의 과발현은 40.7%(24예/59예)였다. HIF-$1{\alpha}$의 과발현은 병리학적 TNM병기(p=0.004), T병기(p=0.020), N병기(p=0.004), 림프관/혈관 침범(p=0.019) 등과 관련이 있었다. 또 혈관내피세포 성장인자의 발현(p<0.001) 및 이상형의 p53의 발현(p=0.040)과 관련성이 있었다. Kaplan-Meier 생존분석에서 HIF-$1{\alpha}$의 과발현이 있는 환자의 5년 생존울은 22%로 HIF-$1{\alpha}$의 저발현 환자의 5년 생존율 61%에 비해 불량한 생존율을 보였고, 단변량분석과 다변량분석에서 HIF-$1{\alpha}$의 발현은 불량한 예후를 나타내는 인자로 관찰되었다. 결론: 이상의 결과로 비소세포 폐암 환자에서 HIF-$1{\alpha}$의 과발현은 종양내 신생혈관의 생성과 림프절 전이와 관련이 있는 표지자로 여겨지며, 수술 후 불량한 예후를 나타내었다.

• Asian Pacific Journal of Cancer Prevention
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• 제17권3호
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• pp.1009-1014
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• 2016

It is not clear how gene polymorphisms affecting drugs can contributes totheir efficacy in multiple myeloma (MM). We here aimed to explore associations among gene polymorphisms of tumor necrosis factor alpha (TNFalpha), nitric oxide synthesis 3 (NOS3) and multi-drug resistance 1 (MDR1), clinical parameters, prognosis and survival in MM patients treated with VAD (vincristine-adriamycine-dexamethasone), MP (mephalane-prednisolone), autolougus stem cell transplantation (ASCT), BODEC (bortezomib-dexamethasone-cyclophosphamide) and TD (thalidomide-dexamethasone). We analyzed TNFalpha, NOS 3 and MDR1 in 77 patients with MM and 77 healthy controls. The genotyping was performed with PCR and/or PCR-RFLP. There was no clinically significant difference between MM and control groups when TNFalpha (-238) and (-857) and MDR1 gene polymorphisms were studied. However, the TNFalpha gene polymorphism (-308) GG genotype (p=0.012) and NOS3 (+894) TT genotype (p=0.008) were more common in the MM group compared to healthy controls. NOS3 (VNTR) AA (p=0.007) and NOS3 (+894) GG genotypes (p=0.004) were decreased in the MM group in contrast. In conclusion, the NOS3 (+894) TT and TNFalpha (-308) GG genotypes may have roles in myeloma pathogenesis.

• Asian Pacific Journal of Cancer Prevention
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• 제14권7호
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• pp.4089-4093
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• 2013

Objective: The rhabdomysarcoma (RMS) is most common soft tissue carcinoma in children, mostly found in the head and neck with high degree of malignancy. The current study aimed to summarize clinical data and evaluate treatment outcome of cases in a single hospital. Methods: Forty-one (24 male, 17 female) children with newly diagnosed RMS in Beijing Tong Ren Hospital were enrolled between November, 2004 and May, 2011. The. Students' t and Chi tests were then performed on retrospectively reviewed clinical data, followed by survival analysis based on the Kaplan Meier method using SPSS 17.0 software. Results: Of all cases, 32 were treated by common chemotherapy, and 3 cases with stage III RMS received high-dose chemotherapy and auto-peripheral blood stem cell transplantation (APBSCT). Side-effects in the former were: I grade for 62.5% (20/32), II grade for 28.1% (9/32), III grade account for 9.275% (3/32). Side-effects of 3 cases with APBSCT: 2 were I grade, 1 was III grade. The median follow-up time of 41 RMS cases was 41 months. Four cases were lost to follow-up, 7 cases recurred, and 5 cases died of cerebral metastasis, witha total survival rate was 86.5% (32/37). CR rate was 67.6% (25/37), PR was 18.9% (7/37). Conclusion: Multidiscipline treatment including chemotherapy, radiotherapy, surgery and auto-PBSCT is highly recommended for pediatric patients with head and neck RMS.