• Environmental Mutagens and Carcinogens
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• v.25 no.1
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• pp.6-12
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• 2005

Many compounds might become activated after absorption of UV light energy. In some cases, the resulting molecule may undergo further biological reaction of toxicological relevance related especially to the photo-carcinogenicity resulting from photo-genotoxicity. However, no regulatory requirements have been issued with the exception of guideline issued by the Scientific Committee of Cosmetology, Commission of the European Communities (SCC/EEC) on the testing of sunscreens for their photo-genotoxicity. Thus, the objectives of this study are to investigate the utility of photo-Ames assay for detecting photo-mutagens, and to evaluate its ability to predict rodent photo-carcinogenicity. Photo-Ames assay was performed on five test substances that demonstrated positive results in photo-carcinogenicity tests: 8-methoxypsoralen (photoactive substance that forms DNA adducts in the presence of ultraviolet A irradiation), chlorpromazine (an aliphatic phenothiazine an a-adr-energic blocking agent), lomefloxacin (an antibiotic in a class of drugs called fluoroquinolones), anthracene (a tricyclic aromatic hydrocarbon a basic substance for production of anthraquinone, dyes, pigments, insecticides, wood preservatives and coating materials) and retinoic acid (a retinoid compound closely related to vitamin A). Out of 5 test substances, 3 showed a positive outcome in photo-Ames assay. With this limited data set, an investigation into the predictive value of this photo-Ames test for determining the photo-carcinogenicity showed that photo-Ames assay has relatively low sensitivity (the ability of a test to predict carcinogenicity). Thus, to determine the use of in vitro genotoxicity tests for prediction of carcinogenicity,' several standard photo-genotoxicity assays should be compared for their suitability in detecting photo-genotoxic compounds.

• Journal of The Korean Society of Clinical Toxicology
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• v.9 no.2
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• pp.88-94
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• 2011

Purpose: Delayed neuropsychological sequelae (DNS) commonly occurs after recovery from acute carbon monoxide poisoning. The aim of this article is to identify the factors associated with DNS development. Methods: We retrospectively evaluated patients, admitted to the medical center emergency department from June 2005 to March 2011, who were suffering from acute carbon monoxide (CO) poisoning. We categorized the patients into two groups - those with DNS, and those without DNS. Multiple regression analysis was performed to identify the factors related to manifestation of DNS. Results: Of the total one hundred fifty seven patients (157) recruited for the study, twenty two (22) developed DNS. Longer CO exposure times and lower GCS scores were positively associated with development of DNS symptoms. Conclusion: Our study identified two potential factors which are predictive of DNS development in CO intoxication, however, more studies are needed. Adequate follow-up after hospital discharge to monitor for and accurately identify manifestation of DNS, is also important.

• BMB Reports
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• v.56 no.9
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• pp.514-519
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• 2023

Methyltransferase-like 3 (METTL3), a key component of the m⁶A methyltransferase complex, regulates the splicing, nuclear transport, stability, and translation of its target genes. However, the mechanism underlying the regulation of METTL3 expression by alternative splicing (AS) remains unknown. We analyzed the expression pattern of METTL3 after AS in human tissues and confirmed the expression of an isoform retaining introns 8 and 9 (METTL3-IR). We confirmed the different intracellular localizations of METTL3-IR and METTL3 proteins using immunofluorescence microscopy. Furthermore, the endogenous expression of METTL3-IR at the protein level was different from that at the mRNA level. We found that 3'-UTR generation by intron retention (IR) inhibited the export of METTL3-IR mRNA to the cytoplasm, which in turn suppressed protein expression. To the best of our knowledge, this is the first study to confirm the regulation of METTL3 gene expression by AS, providing evidence that the suppression of METTL3 protein expression by IR is an integral part of the mechanism by which 3'-UTR generation regulates protein expression via inhibition of RNA export to the cytoplasm.

• International Journal of Stem Cells
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• v.17 no.2
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• pp.120-129
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• 2024

Recent amendments to regulatory frameworks have placed a greater emphasis on the utilization of in vitro testing platforms for preclinical drug evaluations and toxicity assessments. This requires advanced tissue models capable of accurately replicating liver functions for drug efficacy and toxicity predictions. Liver organoids, derived from human cell sources, offer promise as a reliable platform for drug evaluation. However, there is a lack of standardized quality evaluation methods, which hinders their regulatory acceptance. This paper proposes comprehensive quality standards tailored for liver organoids, addressing cell source validation, organoid generation, and functional assessment. These guidelines aim to enhance reproducibility and accuracy in toxicity testing, thereby accelerating the adoption of organoids as a reliable alternative or complementary tool to animal testing in drug development. The quality standards include criteria for size, cellular composition, gene expression, and functional assays, thus ensuring a robust hepatotoxicity testing platform.

• Journal of The Korean Society of Clinical Toxicology
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• v.16 no.2
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• pp.68-74
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• 2018

Purpose: In 2012, a revised guideline for acute acetaminophen overdose was proposed in the UK, recommending that the treatment threshold should be lowered to 100 mcg/ml at 4 hours after ingestion without risk stratification of hepatotoxicity. However, the poison centers in some developing countries do not have laboratory resources to provide serum drug levels in time. The primary aim of the study is to evaluate the cut-off value of reported dose per kilogram to determine when N-acetylcysteine treatment is warranted under the revised guideline. Methods: Data were collected retrospectively from the toxicology registry of an urban emergency medical center between 1st January 2010 and 30th June 2017. Inclusion criteria were single acute overdose of more than 75 mg/kg in 15 hours from ingestion and over 14 years of age. Subgroups were created by 25 mg/kg increments of reported dose, then sensitivity, specificity, positive predictive value and negative predictive value were calculated for the cut-off values of 100 mg/kg, 125 mg/kg, 150 mg/kg and 175 mg/kg for toxic serum level over '100-treatment line'. Results: A total of 99 patients were enrolled in the study; 24 patients showed toxic serum levels (24.2%). Zero of 17 patients with an ingestion dose under 100 mg/kg showed toxic level (0%), and 0 of 15 under 125 mg/kg (0%), 2 of 14 under 150 mg/kg (14.3%), and 4 of 12 under 175 mg/kg (33.3%) had toxic levels. The higher the ingested dose per kilogram of weight, the higher the frequency of the toxic serum concentration on the first test (${\chi}^2$ test for trend, ${\chi}^2=22.66$, p-value<0.001) and the sensitivity of each value was 100%, 100%, 92% and 76%. Conclusion: In acute single acetaminophen intoxication, the ingestion dose of 100 mg/kg of weight will be useful in determining the need for the N-acetylcysteine antidote in the indigent laboratory environment.

• Asian Pacific Journal of Cancer Prevention
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• v.13 no.12
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• pp.6039-6045
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• 2012

This study was conducted to assess the predictive value of p-glycoprotein (p-gp) and p53 immunoexpression in human papillomavirus (HPV) infected cases of cervical dysplasia. Expression of both p-gp and p53 proteins was detected in cervical smears from 177 squamous intraepithelial lesions (SIL) cases along with 183 "atypical squamous cells of unknown significance" (ASCUS) and 150 normal cases. HPV 16 and 18 infection was detected by polymerase chain reaction using type-specific primers for HPV sub-types. There were no significant detectable p53 and p-gp expression in the normal cervix smears (p>0.05). In the ASCUS group 10 cases were positive for both p53 and p-gp immunoreactivity. In cervical dysplasia cases, p53 was positive in 86 (48.58%) while p-gp was positive in 93 (52.54%) and the two markers showed a highly significant correlation (r=0.92, p<0.001). Expression of p53 and p-gp was associated with grade of SIL (p<0.001). A positive correlation between the presence of HPV and expression of proteins p53 and p-gp in smears of patients with cervical lesions was also noted (p<0.001). Thus, p53 and p-gp immunostaining in cervical smears may act as an auxiliary biomarker for detection of HPV-associated cervical lesions. Additionally, a significant positive correlation between ascending grades of SIL and labeling indices of markers suggests that p53 and p-gp can be used as an adjunct to cytomorphological interpretation of conventional cervical Pap smears.

• Toxicological Research
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• v.28 no.2
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• pp.81-91
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• 2012

Many risk factors exist for chemotherapy-induced nausea and vomiting (CINV). This study utilized a multivariate projection technique to identify which risk factors were predictive of CINV in clinical practice. A single-centre, prospective, observational study was conducted from January 2007~July 2010 in Singapore. Patients were on highly (HECs) and moderately emetogenic chemotherapies with/without radiotherapy. Patient demographics and CINV risk factors were documented. Daily recording of CINV events was done using a standardized diary. Principal component (PC) analysis was performed to identify which risk factors could differentiate patients with and without CINV. A total of 710 patients were recruited. Majority were females (67%) and Chinese (84%). Five risk factors were potential CINV predictors: histories of alcohol drinking, chemotherapy-induced nausea, chemotherapy-induced vomiting, fatigue and gender. Period (ex-/current drinkers) and frequency of drinking (social/chronic drinkers) differentiated the CINV endpoints in patients on HECs and anthracycline-based, and XELOX regimens, respectively. Fatigue interference and severity were predictive of CINV in anthracycline-based populations, while the former was predictive in HEC and XELOX populations. PC analysis is a potential technique in analyzing clinical population data, and can provide clinicians with an insight as to what predictors to look out for in the clinical assessment of CINV. We hope that our results will increase the awareness among clinician-scientists regarding the usefulness of this technique in the analysis of clinical data, so that appropriate preventive measures can be taken to improve patients' quality of life.

• Molecular & Cellular Toxicology
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• v.2 no.3
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• pp.216-221
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• 2006

The cholinesterase-inhibiting organophosphorous (OP) compounds known as nerve agents are highly toxic. The principal toxic mechanism of OP compounds is the inhibition of acethylcholine esterase (AChE) by phosphorylation of its catalytic site. The reversible competitive inhibition of AChE may prevent the subsequent OP intoxication. In this study, three-dimensional quantitative structure-activity relationship (3D-QSAR) was performed to investigate the relationship between the 29 compounds with structural diversity and their bioactivities against AChE. In particular, predictive models were constructed using the comparative molecular field analysis (CoMFA) and comparative molecular similarity indices analysis (CoMSIA). The results indicate reasonable model for CoMFA ($q^{2}=0.453,\;r^{2}=0.697$) and CoMSIA ($q^{2}=0.518,\;r^{2}=0.696$). The presence of steric and hydophobic group at naphtyl moiety of the model may lead to the design of improved competitive inhibitors for organophosphorous intoxication.

• Journal of The Korean Society of Clinical Toxicology
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• v.19 no.2
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• pp.72-82
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• 2021

Purpose: A high anion gap (AG) is known to be a significant risk factor for serious acid-base imbalances and death in acute poisoning cases. The strong ion difference (SID), or strong ion gap (SIG), has recently been used to predict in-hospital mortality or acute kidney injury (AKI) in patients with systemic inflammatory response syndrome. This study presents a comprehensive acid-base analysis in order to identify the predictive value of the SIG for disease severity in severe poisoning. Methods: A cross-sectional observational study was conducted on acute poisoning patients treated in the emergency intensive care unit (ICU) between December 2015 and November 2020. Initial serum electrolytes, base deficit (BD), AG, SIG, and laboratory parameters were concurrently measured upon hospital arrival and were subsequently used along with Stewart's approach to acid-base analysis to predict AKI development and in-hospital death. The area under the receiver operating characteristic curve (AUC) and logistic regression analysis were used as statistical tests. Results: Overall, 343 patients who were treated in the intensive care unit were enrolled. The initial levels of lactate, AG, and BD were significantly higher in the AKI group (n=62). Both effective SID [SIDe] (20.3 vs. 26.4 mEq/L, p<0.001) and SIG (20.2 vs. 16.5 mEq/L, p<0.001) were significantly higher in the AKI group; however, the AUC of serum SIDe was 0.842 (95% confidence interval [CI]=0.799-0.879). Serum SIDe had a higher predictive capacity for AKI than initial creatinine (AUC=0.796, 95% CI=0.749-0.837), BD (AUC=0.761, 95% CI=0.712-0.805), and AG (AUC=0.660, 95% CI=0.607-0.711). Multivariate logistic regression analyses revealed that diabetes, lactic acidosis, high SIG, and low SIDe were significant risk factors for in-hospital mortality. Conclusion: Initial SIDe and SIG were identified as useful predictors of AKI and in-hospital mortality in intoxicated patients who were critically ill. Further research is necessary to evaluate the physiological nature of the toxicant or unmeasured anions in such patients.

• Journal of The Korean Society of Clinical Toxicology
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• v.16 no.2
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• pp.61-67
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• 2018

Purpose: To evaluate the association between neutrophil-to-lymphocyte ratio (NLR) and occurrence of aspiration pneumonia in drug intoxication (DI) patients in the emergency department (ED) and to evaluate the relationship between NLR and length of hospital admission/intensive care unit (ICU) admission Methods: A total of 466 patients diagnosed with DI in the ED from January 2016 to December 2017 were included in the analysis. The clinical and laboratory results, including NLR, were evaluated as variables. NLR was calculated as the absolute neutrophil count/absolute lymphocyte count. To evaluate the prognosis of DI, data on the development of aspiration pneumonia were obtained. Also, we evaluated the relationship between NLR and length of hospital admission and between NLR and length of ICU admission. Statistically, multivariate logistic regression analyses, receiver-operating characteristic (ROC) curve analysis, and Pearson's correlation (${\rho}$) were performed. Results: Among the 466 DI patients, 86 (18.5%) developed aspiration pneumonia. Multivariate logistic regression analysis revealed NLR as an independent factor in predicting aspiration pneumonia (odds ratio, 1.7; p=0.001). NLR showed excellent predictive performance for aspiration pneumonia (areas under the ROC curves, 0.815; cut-off value, 3.47; p<0.001) with a sensitivity of 86.0% and a specificity of 72.6%. No correlations between NLR and length of hospital admission (${\rho}=0.195$) and between NLR and length of ICU admission (${\rho}=0.092$) were observed. Conclusion: The NLR is a simple and effective marker for predicting the occurrence of aspiration pneumonia in DI patients. Emergency physicians should be alert for aspiration pneumonia in DI patients with high NLR value (>3.47).