• Tuberculosis and Respiratory Diseases
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• 제66권3호
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• pp.198-204
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• 2009

연구배경: 다제내성결핵 치료에서 감수성으로 증명된 1차 항결핵제는 가장 항결핵효과가 큰 약제로 알려져 있다. 본 연구는 다제내성결핵 환자에서 표준 1차 항결핵제사용 후 1차 항결핵제에 대한 추가 내성 획득의 빈도와 그 위험 인자를 알아보고자 시행되었다. 방 법: 2004년 1월에서 2008년 5월까지 국립마산결핵병원에서 약제감수성 검사가 보고되기 전 표준 1차 항결핵제로 치료받은 다제내성결핵 환자 중에서 1차 항결핵제 치료 전과 1차 항결핵제 치료 후의 연속된 두 시점의 약제 감수성 검사 결과가 모두 있는 환자를 대상으로 하여 의무기록을 후향적으로 검토하였다. 결 과: 표준 1차 항결핵제로 치료 받은 41명 중 14명 (34.1%)에서 ethambutol (EMB) 혹은 pyrazinamide (PZA)에 대한 추가 내성이 획득되었다. 치료 전 isoniazid (INH), rifampicin (RFP)에만 내성을 보였던 11명 중 3명(27.3%)에선 EMB와 PZA에 동시 내성, 3명(27.3%)에선 PZA에 추가 내성이 획득되었다. INH, RFP, EMB에 내성을 보인 18명 중 6명(33.3%)에서 PZA에, INH, RFP, PZA에 내성을 보인 6명 중 2명(33.3%)에서 EMB에 추가 내성이 획득되었다. 대상 환자 중 10명(24.4%)에서 1차 항결핵제 치료 전 내성이었던 약제가 치료 후 감수성으로 전환되었다. 추가 내성획득과 연관된 통계학적으로 유의한 위험인자를 발견할 수 없었다. 결 론: 우리나라의 다제내성결핵 치료에서 1차 항결핵제는 추가 획득 내성의 위험을 고려하여 주의 깊게 사용해야 할 것으로 사료된다.

• Tuberculosis and Respiratory Diseases
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• 제75권5호
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• pp.188-198
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• 2013

Over the past decade, several kinase inhibitors have been approved based on their clinical benefit in cancer patients. Unfortunately, in many cases, patients develop resistance to these agents via secondary mutations and alternative mechanisms. To date, several major mechanisms of acquired resistance, such as secondary mutation of the epidermal growth factor receptor (EGFR) gene, amplification of the MET gene and overexpression of hepatocyte growth factor, have been reported. This review describes the recent findings on the mechanisms of primary and acquired resistance to EGFR tyrosine kinase inhibitors and acquired resistance to anaplastic lymphoma kinase inhibitors, primarily focusing on non-small cell lung carcinoma.

• Asian Pacific Journal of Cancer Prevention
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• 제15권1호
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• pp.205-213
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• 2014

The outcomes of first-generation EGFR-TKIs (Gefitnib and Erlotinib) have shown great advantages over traditional treatment strategies in patients with non-small cell lung cancer (NSCLC), but unfortunately we have to face the situation that most patients still fail to respond in the long term despite initially good control. Up to now, the mechanism of acquired resistance to EGFR-TKIs has not been fully clarified. Herein, we sought to compile the available clinical reports in the hope to better understanding the subsequent treatment choices, particularly on whether restoring after a drug holiday or switching to another EGFR-TKI is the better option after failure of one kind of EGFR-TKI.

• Journal of Microbiology
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• 제44권3호
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• pp.336-343
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• 2006

We compared the antimicrobial resistance and clonal relationships among the community-acquired (CA) and hospital-acquired (HA) methicillin-resistant Staphylococcus aureus (MRSA) strains that were isolated from blood cultures in a university hospital over a 4-year period. A total of 131 MRSA isolates, including 28 CA-MRSA and 103 HA-MRSA strains, were identified; antimicrobial susceptibility testing indicated that the CA-MRSA isolates were more susceptible to erythromycin (21 % vs 6% ; P=0.02), clindamycin (46% vs 12%; P<0.01), ciprofloxacin (43% vs 11%; P<0.01), and gentamicin (43% vs 6%; P<0.01) than were the HA-MRSA isolates. Pulsed-field gel electrophoresis (PFGE) typing and antimicrobial resistance profiles separated the 20 CA-MRSA isolates into 14 and 10 different patterns, respectively, and the 53 HA-MRSA isolates were separated into 24 and 7 different patterns, respectively. Twenty-one (40%) of the 53 HA-MRSA isolates belonged to two predominant PFGE types, and most of them showed multi-drug resistant patterns. Four (20%) of the 20 CA-MRSA and 10 (19%) of the 53 HA-MRSA isolates fell into two common PFGE patterns, and each of them showed the same multi-drug resistant pattern. This study suggests that, although the CA-MRSA blood isolates showed diverse PFGE and antimicrobial resistance patterns, some of these isolates may have originated from the HA-MRSA strains.

• Biomolecules & Therapeutics
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• 제19권2호
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• pp.174-180
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• 2011

Experiments were carried out to determine the role of Raf-1 kinase in the development of drug resistance to paclitaxel in v-H-ras transformed NIH 3T3 fibroblasts (Ras-NIH 3T3). We established a multidrug-resistant cell line (Ras-NIH 3T3/Mdr) from Ras-NIH 3T3 cells by stepwise increases in paclitaxel. Drug sensitivity assays indicated that the $IC_{50}$ value for drug-resistant Ras-NIH 3T3/Mdr cells was more than 1 ${\mu}M$ paclitaxel, 10- or more-fold higher than for the parental Ras-NIH 3T3 cells. Western blot and RT-PCR analysis showed that the drug efflux pump a P-glycoprotein were highly expressed in Ras-NIH 3T3/Mdr cells, while not being detectable in Ras-NIH 3T3 cells. Additionally, verapamil, which appears to inhibit drug efflux by acting as a substrate for P-glycoprotein, completely reversed resistance to paclitaxel in Ras-NIH 3T3/Mdr cell line, indicating that resistance to paclitaxel is associated with overexpression of the multidrug resistance gene. Interestingly, Ras-NIH 3T3/Mdr cells have higher basal Raf-1 activity compared to Ras-NIH 3T3 cells. Unexpectedly, however, the colocalization of Raf-1 and its negative regulator Spry2 was less observed in cytoplasm of Ras-NIH 3T3/Mdr cells due to translocation of Spry2 around the nucleus in the perinuclear zone, implying that Raf-1 may be released from negative feedback inhibition by interacting with Spry2. We also showed that shRNA-mediated knockdown of Raf-1 caused a moderate increase in cell susceptibility to paclitaxel. Thus, the results presented here suggest that a Raf-1-dependent pathway plays an important role in the development of acquired drug-resistance.

• Journal of Microbiology
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• 제45권1호
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• pp.64-68
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• 2007

In this study we examined the multi-drug resistance profiles of the tetracycline (TC) resistant genus Vibrio to determine its susceptibility to two ${\beta}-lactams$, ampicillin (ABPC), and mecillinam (MPC), as well as to macrolide, erythromycin (EM). The results showed various patterns of resistance among strains that were isolated from very close geographical areas during the same year, suggesting diverse patterns of drug resistance in environmental bacteria from this area. In addition, the cross-resistance patterns suggested that the resistance determinants among Vibrio spp. are acquired differently within the sediment and seawater environments.

• 대한약학회:학술대회논문집
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• 대한약학회 2003년도 Proceedings of the Convention of the Pharmaceutical Society of Korea Vol.2-2
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• pp.167.2-168
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• 2003

Anticancer drug resistance occasionally occurs in malignant hematologic diseases such as acute myelocytic leukemia (AML) treated with chemotherapy and is a major problem to complete remission. Malignant cells primarily induce intrinsic resistance to treatment of anticancer drug, but gradually obtain acquired resistance to cytotoxic activities of chemotherapy. In this study, we monitored the expression profiles of doxorubicin resistance-related genes in AML-2/DX100, a doxorubicin-resistant human acute myelocytic leukemia cell line. (omitted)

• Tuberculosis and Respiratory Diseases
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• 제59권6호
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• pp.619-624
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• 2005

연구배경 : 치료 경력이 있는 환자의 약제 내성은 진료의사의 처방의 적절성 및 환자의 복용 순응도를 복합적으로 나타내어 주는 지표가 될 수 있으므로, 우리나라에서 재치료 대상 결핵 환자에서 장기간의 약제내성률 추이를 파악하고자 하였다. 방 법 : 연도별 보건소 등록환자의 약제감수성 검사 결과 및 결핵연구원의 전산 입력된 자료를 활용하여 1981년부터 2004년 사이에 주요 약제에 대한 내성률의 변화를 분석하였다. 결 과 : Isoniazid 내성은 90%에서 20%로 감소하였다. Ethambutol 내성률도 45%에서 6%로 감소하였다. Rifampin 내성률은 13%에서 28%까지 증가하다가 13%까지 감소하였다. 다제내성률은 rifampin 내성률보다 약 2-3% 낮았다. Pyrazinamide 내성률은 5% 미만에서 10% 정도까지 증가하였다가 다시 5%까지 감소하였다. 2차약제에 대한 내성률은 1-2% 정도였다. 내성 빈도는 남녀 간에 차이가 없었으며, 대도시 지역이 중소도시/농촌지역보다 낮은 약제 내성률을 보였다. 결 론 : 우리나라보건소에 등록되는 재치료 대상 결핵 환자의 주요 항결핵 약제에 대한 내성률은 2004년을 기준으로 isoniazid 20%, rifampin 13%, 다제내성 11%, ethambutol 6%, pyrazinamide 5% 기타 2차 항결핵제에 1-3%로 나타났으며 1981년 이후 모든 항결핵 약제에서 그 내성률이 유의하게 감소하고 있었다.

• Genomics & Informatics
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• 제19권1호
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• pp.2.1-2.10
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• 2021

BRAF inhibitors (e.g., vemurafenib) are widely used to treat metastatic melanoma with the BRAF V600E mutation. The initial response is often dramatic, but treatment resistance leads to disease progression in the majority of cases. Although secondary mutations in the mitogen-activated protein kinase signaling pathway are known to be responsible for this phenomenon, the molecular mechanisms governing acquired resistance are not known in more than half of patients. Here we report a genome- and transcriptome-wide study investigating the molecular mechanisms of acquired resistance to BRAF inhibitors. A microfluidic chip with a concentration gradient of vemurafenib was utilized to rapidly obtain therapy-resistant clones from two melanoma cell lines with the BRAF V600E mutation (A375 and SK-MEL-28). Exome and transcriptome data were produced from 13 resistant clones and analyzed to identify secondary mutations and gene expression changes. Various mechanisms, including phenotype switching and metabolic reprogramming, have been determined to contribute to resistance development differently for each clone. The roles of microphthalmia-associated transcription factor, the master transcription factor in melanocyte differentiation/dedifferentiation, were highlighted in terms of phenotype switching. Our study provides an omics-based comprehensive overview of the molecular mechanisms governing acquired resistance to BRAF inhibitor therapy.

• Asian Pacific Journal of Cancer Prevention
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• 제15권18호
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• pp.7913-7917
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• 2014

Apoptotic cell death plays a predominant role in histone deacetylase (HDAC) inhibitor-induced cytotoxicity. Nuclear morphological changes and activation of apoptotic executors are involved in CTS203-induced cell death. However, emerging issues of HDAC inhibitor-resistance have been observed in patients. Herein, MCF-7 cells were continuously exposed to CTS203 until the derived cells could proliferate normally in its presence. The newly obtained CTS203-resistant cells were nominated as MCF-7/203R. Compared to MCF-7 original cells, the MCF-7/203R cells were less sensitive to CTS203-induced apoptosis, with a minimal 6-fold higher $IC_{50}$ value. In contrast, the expression of Beclin-1 was dramatically up-regulated, positively correlated to the acquisition of CTS203-resistance. Our results revealed the participation of autophagy in acquired HDAC inhibitor-resistance and further identified Beclin-1 as a promising target for anti-drug resistance.