• 대한의용생체공학회:의공학회지
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• 제43권1호
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• pp.19-26
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• 2022

The Comprehensive in vitro Proarrhythmic Assay(CiPA) project was launched for solving the hERG assay problem of being classified as high-risk groups even though they are low-risk drugs due to their high sensitivity. CiPA presented a protocol to predict drug toxicity using physiological data calculated based on the in-silico model. in this study, features calculated through the in-silico model are analyzed for correlation of changing action potential in the near future, and features are verified through predictive performance according to drug datasets. Using the O'Hara Rudy model modified by Dutta et al., Pearson correlation analysis was performed between 13 features(dVm/dtmax, APpeak, APresting, APD90, APD50, APDtri, Ca_peak, Ca_resting, CaD90, CaD50, CaDtri, qNet, qInward) calculated at 100 pacing, and between dVm/d_{tmax_repol} calculated at 1,000 pacing, and linear regression analysis was performed on each of the 12 training drugs, 16 verification drugs, and 28 drugs. Indicators showing high coefficient of determination(R²) in the training drug dataset were qNet 0.93, AP resting 0.83, APDtri 0.78, Ca resting 0.76, dVm/dt_max 0.63, and APD90 0.61. The indicators showing high determinants in the validated drug dataset were APDtri 0.94, APD90 0.92, APD50 0.85, CaD50 0.84, qNet 0.76, and CaD90 0.64. Indicators with high coefficients of determination for all 28 drugs are qNet 0.78, APD90 0.74, and qInward 0.59. The indicators vary in predictive performance depending on the drug dataset, and qNet showed the same high performance of 0.7 or more on the training drug dataset, the verified drug dataset, and the entire drug dataset.

• Biomolecules & Therapeutics
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• 제3권3호
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• pp.242-244
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• 1995

In vitro cell culture system has been proposed as a promising alternative model to in vivo skin irritation test. These studies were performed to screen the cytotoxicity effects of surfactants using normal human skin fibroblasts. Cell membrane integrity assessed by the leakage of lactate dehydrogenase (LDH) and mitochondrial integrity by MTT [3-(4, 5-dimethylthiazol-2-yl)-2, 5-diphenyl tetrazolium bromides reduction test were affected in a dose dependent manner. The irritation potential of surfactants to human skin patch test, and the changes of capillary permeability by rabbit intradermal safety test were assessed as in vivo methods. Our results suggest that LDH leakage assay and MTT reduction test using cultured human fibroblasts could be predictive for the irritancy of various surfactants in human, and LDH assay is superior correlated with in vivo test (r=0.886) to MTT test with in vivotest (r=0.757).

• Asian Pacific Journal of Cancer Prevention
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• 제16권7호
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• pp.2915-2921
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• 2015

Background: Some recent clinical trials have been conducted to evaluate a combination of EGFR- TKI with chemotherapy for advanced NSCLC patients as second-line therapy, but the results on the efficacy of such trials are inconsistent. The aim of this meta-analysis was to evaluate the efficacy and safety of combination of EGFR-TKI and chemotherapy for patients with advanced NSCLC who failed first-line treatment. Materials and Methods: We searched relative trials from PubMed, EMBASE, ASCO Abstracts, ESMO Abstracts, Cochrane Library and Clinical Trials.gov. Outcomes analyzed were overall response rate (ORR), progression- free survival (PFS), overall survival (OS) and major toxicity. Results: Seven trails eventually were included in this meta-analysis, covering 1,168 patients. The results showed that the combined regimen arm had a significant higher ORR (RR 1.76 [1.16, 2.66], p=0.007) and longer PFS (HR 0.75 [0.66-0.85], p<0.00001), but failed to show effects on OS (HR 0.88 [0.68-1.15], p=0.36). In terms of subgroup results, continuation of EGFR-TKI in addition to chemotherapy after first-line EGFR-TKI resistance confered no improvement in ORR (RR 0.95 [0.68, 1.33], p=0.75) and PFS (HR 0.89[0.69, 1.15], p=0.38), and OS was even shorter (HR1.52 [1.05-2.21], p=0.03). However, combination therapy with EGFR-TKI and chemotherapy after failure of first-line chemotherapy significantly improved the ORR (RR 2.06 [1.42, 2.99], p=0.0002), PFS (HR 0.71 [0.61, 0.82], p<0.00001) and OS (HR 0.74 [0.62-0.88], p=0.0008), clinical benefit being restricted to combining EGFR-TKI with pemetrexed, but not docetaxel. Grade 3-4 toxicity was found at significantly higher incidence in the combined regimen arm. Conclusions: Continuation of EGFR-TKI in addition to chemotherapy after first-line EGFR-TKI resistance should be avoided. Combination therapy of EGFR-TKI and pemetrexed for advanced NSCLC should be further investigated for prognostic and predictive factors to find the group with the highest benefit of the combination strategy.

• Asian Pacific Journal of Cancer Prevention
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• 제15권19호
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• pp.8383-8390
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• 2014

Background: Although the predictive value of the excision repair cross-complementing group 1 (ERCC1) C118T polymorphism in clinical outcomes of patients with colorectal cancer (CRC) receiving oxaliplatin-based chemotherapy has been evaluated in numerous published studies, the conclusions are conflicting. Therefore, we performed the present meta-analysis to determine the precise role of the ERCC1 C118T polymorphism in this clinical situation and help optimize individual chemotherapy. Materials and Methods: A multiple search strategy was used to identify eligible studies. Pooled odds ratios (ORs) and their 95% confidence intervals (CIs) were used to estimate objective response and oxaliplatin-induced toxicity, with hazard ratios (HRs) with 95%CIs for progression-free survival (PFS) and overall survival (OS). Results: A total of 22 studies including 2,846 CRC patients were eligible in the analysis. Overall, no significant correlation was found between the ERCC1 C118T polymorphism and objective response to oxaliplatin-based chemotherapy, in all patients or in the Asian and Caucasian subgroups. However, the pooled analysis showed that the PFS and OS were significantly shorter in patients who carried T/T or T/C genotypes of ERCC1 C118T as compared to the C/C genotype. On stratified analysis by ethnicity, the ERCC1 118T allele was associated with a favorable prognosis in Caucasians (PFS, HR=0.58, 95%CI: 0.24-1.44; OS, HR=0.38, 95%CI: 0.22-0.64) but an unfavorable prognosis in Asians (PFS, HR=2.49, 95%CI: 1.87-3.33; OS, HR=2.63, 95%CI: 1.87-3.69) based on a dominant model. In addition, we failed to find a statistically significant impact of ERCC1 C118T polymorphism on oxaliplatin-induced toxicity. Conclusions: The ERCC1 C118T polymorphism may have prognostic value in patients with CRC undergoing oxaliplatin-based chemotherapy.

• Radiation Oncology Journal
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• 제25권2호
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• pp.109-117
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• 2007

목 적: 유방암 환자에서 보조적 방사선치료 후 호흡기 증상을 동반한 방사선 폐렴(SRP) 및 방사선학적 폐 독성(RPT)의 빈도 및 이에 영향을 미치는 예측인자를 알아보고자 하였다. 특히 3차원 방사선계획에서 얻은 선량체적히스토그람(DVH) 인자와 RTP의 상관관계를 중심으로 분석해보고자 하였다. 대상 및 방법: 2003년 9월부터 2006년 2월까지 171명의 환자가 유방암으로 수술 후 방사선치료를 받았다. 2개의 tangential photon 조사야가 통상적으로 사용되었고, 액와부 림프절 전이 정도에 따라 anterior oblique photon 조사야를 추가하였다. 유방 보존술 후 보조적 방사선치료를 받은 침윤성 유방암 환자에는 전자선을 이용한 boost가 적용되었다. 방사선 치료 후의 정기추적 흉부 단순촬영소견을 흉부방사선전문의와 함께 검토, 분석하였다. RTOG 특성기준 및 modified WHO grading system을 적용하였다. 조사받은 방사선량에 따라 $V_{15},\;V_{20},\;V_{30}$ 및 mean lung dose (MLD)를 구하되, 동측 폐를 tangential 및 SCL 영역으로 구분하여, 각각의 DVH parameters 즉 $V_{15\;TNGT},\;V_{20\;TNGT},\;V_{30\;TNGT},\;MLD_{TNGT}$ 및 $V_{15\;SCL},\;V_{20\;SCL},\;V_{30\;SCL},\;MLD_{SCL}$을 구하여 RPT와의 상관관계를 분석하였다. 결 과: 호흡기 증상을 동반한 방사선 폐렴(SRP)이 4예(2.1%)에서 발생하였다(RTOG grade 3가 3예 grade 1이 1예). 나이 흡연여부, 기존폐질환유무, 항암요법, 호르몬치료, regional RT 여부 등은 SRP와 무관하였다. 3-RTP가 시행된 137예 중 13.9%에서 tangential 영역에 RPT가 발생하였다. Regional RT를 받은 59 중 49.2%에서 SCL 영역에 RPT가 발생하였다. Regional RT 유무(p<0.001), 환자의 나이(p=0.039), V15 TNGT를 제외한 모든 DVH parameter들이 RPT와 유의한 상관관계를 나타내었다. $MLD_{TNGT}$는 TNGT 영역의 RPT를, $V_{15\;SCL}$는 SCL 영역의 RPT를 예측하기에 적합한 것으로 분석되었다. 결 론: 본 연구에서 SRP의 빈도는 매우 낮았다. Regional RT 여부와 환자의 나이, DVH parameter들이 RPT와 유의한 상관관계를 나타내었으며, $MLD_{TNGT}$는 TNGT 영역에서, $V_{15\;SCL}$는 SCL 영역에서 RPT의 유의한 예측인자였다.

• 대한임상독성학회지
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• 제2권2호
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• pp.72-76
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• 2004

Purpose: Dealing patients with organophosphate poisoning, cholinesterase level has been used as a diagnostic and prognostic value. But there are some controversies that the cholinesterase level is significantly related to the severity or prognosis of acute organophosphate poisoning. We evaluated the correlation between initial serum level of cholinesterase and APACHE II score as an index for severity, and we assessed cholinesterase levels for predicting value of weaning from mechanical ventilation. Method: From August 1996 to March 2003, 23 patients with organophosphate poisoning who needed ventilatory care were enrolled. Retrospective review was done for the serum level of cholinesterase, APACHE II score, and the duration of ventilatory care. The percentage of measured serum cholinesterase to median normal value was used to standardize cholinesterase levels from different laboratories. Result: There were tendencies that the lower initial serum of cholinesterase, the higher the APACHE II score (r=0.297) and the longer the duration of mechanical ventilation (r=-0.204), but they were not significant (p=0.264 and p=0.351 respectively). In 9 patients whose serum cholinesterase level were checked at the time of weaning, mean of measured cholinesterase level was $10.3\pm7.60\%$ of normal value. Conclusion: There was no significant relationship between initial level of serum cholinesterase and severity or duration of mechanical ventilation. General health status of patient, amount of ingestion, toxicity of agent should be considered as important factors for severity of poisoning. And the decision of weaning should be based not solely on the cholinesterase level but on the consideration of general and respiratory state of individual patients.

• Genomics & Informatics
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• 제8권1호
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• pp.50-57
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• 2010

Mercuric chloride, a model nephrotoxicant was used to elucidate time- and dose- dependent global gene expression changes associated with proximal tubular toxicity. Rat kidney cell lines NRK-52E cells were exposed for 2, 6 and 12 hours and with 3 different doses of mercuric chloride. Cell viability assay showed that mercuric chloride had toxic effects on NRK-52E cells causing 20% cell death (IC20) at $40{\mu}M$ concentration. We set this IC20 as high dose concentration and 1/5 and 1/25 concentration of LC20 were used as mid and low concentration, respectively. Analyses of microarray data revealed that 738 genes were differentially expressed (more than two-fold change and p<0.05) by low concentration of mercuric chloride at least one time point in NRK-52E cells. 317 and 2,499 genes were differentially expressed at mid and high concentration of mercuric chloride, respectively. These deregulated genes showed a primary involvement with protein trafficking (CAV2, CANX, CORO1B), detoxification (GSTs) and immunity and defense (HMOX1, NQO1). Several of these genes were previously reported to be up-regulated in proximal tubule cells treated with nephrotoxicants and might be aid in promoting the predictive biomarkers for nephrotoxicity.

• Radiation Oncology Journal
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• 제36권4호
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• pp.276-284
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• 2018

Purpose: Traditionally, three-dimensional conformal radiation therapy (3D-CRT) is used for neoadjuvant chemoradiation in locally advanced rectal cancer. Intensity-modulated radiation therapy (IMRT) was later developed for more conformal dose distribution, with the potential for reduced toxicity across many disease sites. We sought to use the National Cancer Database (NCDB) to examine trends and predictors for IMRT use in rectal cancer. Materials and Methods: We queried the NCDB from 2004 to 2015 for patients with rectal adenocarcinoma treated with neoadjuvant concurrent chemoradiation to standard doses followed by surgical resection. Odds ratios were used to determine predictors of IMRT use. Univariable and multivariable Cox regressions were used to determine potential predictors of overall survival (OS). Propensity matching was used to account for any indication bias. Results: Among 21,490 eligible patients, 3,131 were treated with IMRT. IMRT use increased from 1% in 2004 to 22% in 2014. Predictors for IMRT use included increased N stage, higher comorbidity score, more recent year, treatment at an academic facility, increased income, and higher educational level. On propensity-adjusted, multivariable analysis, male gender, increased distance to facility, higher comorbidity score, IMRT technique, government insurance, African-American race, and non-metro location were predictive of worse OS. Of note, the complete response rate at time of surgery was 28% with non-IMRT and 21% with IMRT. Conclusion: IMRT use has steadily increased in the treatment of rectal cancer, but still remains only a fraction of overall treatment technique, more often reserved for higher disease burden.

• 대한한의학회지
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• 제31권2호
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• pp.109-113
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• 2010

Objectives: Liver function tests are used as screening tests for liver injuries, but their inaccuracy on positive predictive values can result in numerous false positive results. We investigated the incidence of liver function test abnormalities of patients who came to an oriental medicine hospital, in order to present a practical way to rule out false positive results for other studies designed to investigate the safety of Korean herb medicine. Methods: We analyzed the medical records and liver function test results proceeded at admission of all in-patients admitted to Jaseng Oriental Medicine Hospital, from July 2008 to June 2009. Results: Among 1,117 inpatients, 941 executed liver function tests on admission, and 40 were excluded due to their diagnosed liver disease. 747 (82.9%) of 901 enrolled patients were within the normal range of all liver function tests, and 140 (15.5%) and 14 (1.6%) were classified as "abnormalities of liver tests" and "liver injury" respectively, according to the CIOMS (Council for International Organizations of Medical Sciences) criteria. Conclusions: According to the results, among the outcomes of liver function tests proceeded among the patients admitted to the oriental medicine hospital, excluding who were diagnosed with liver disease, 17.1% showed abnormality. This means simple liver function test results are not sufficient in determining liver toxicity of Korean herb medicine (KHM).

• Journal of Gastric Cancer
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• 제19권4호
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• pp.375-392
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• 2019

Preoperative chemo- and radiotherapeutic strategies followed by surgery are currently a standard approach for treating locally advanced gastric and esophagogastric junction cancer in Western countries. However, in a large number of cases, the tumor is extremely resistant to these treatments and the patients are exposed to unnecessary toxicity and delayed surgical therapy. The current clinical trials evaluating the combination of preoperative systemic therapies with modern targeted and immunotherapeutic agents represent a unique opportunity for identifying predictive biomarkers of response to select patients that would benefit the most from these treatments. However, it is of utmost importance that these potential biomarkers are corroborated by extensive preclinical and translational research. The aim of this review article is to present the most promising biomarkers of response to classic chemotherapeutic, anti-HER2, antiangiogenic, and immunotherapeutic agents that can be potentially useful for personalized preoperative systemic therapies in gastric cancer patients.