• Asian Pacific Journal of Cancer Prevention
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• 제16권18호
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• pp.8191-8196
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• 2016

Inhibition of EGFR-EGF interactions forms an important therapeutic rationale in treatment of non-small cell lung carcinoma. Established inhibitors have been successful in reducing proliferative processes observed in NSCLC, however patients suffer serious side effects. Considering the narrow therapeutic window of present EGFR inhibitors, the present study centred on identifying high efficacy EGFR inhibitors through structure based virtual screening strategies. Established inhibitors - Afatinib, Dacomitinib, Erlotinib, Lapatinib, Rociletinib formed parent compounds to retrieve similar compounds by linear fingerprint based tanimoto search with a threshold of 90%. The compounds (parents and respective similars) were docked at the EGF binding cleft of EGFR. Patch dock supervised protein-protein interactions were established between EGF and ligand (query and similar) bound and free states of EGFR. Compounds ADS103317, AKOS024836912, AGN-PC-0MXVWT, GNF-Pf-3539, SCHEMBL15205939 were retrieved respectively similar to Afatinib, Dacomitinib, Erlotinib, Lapatinib, Rociletinib. Compound-AGN-PC-0MXVWT akin to Erlotinib showed highest affinity against EGFR amongst all the compounds (parent and similar) assessed in the study. Further, AGN-PC-0MXVWT brought about significant blocking of EGFR-EGF interactions in addition showed appreciable ADMET properties and pharmacophoric features. In the study, we report AGN-PC-0MXVWT to be an efficient and high efficacy inhibitor of EGFR-EGF interactions identified through computational approaches.

• Tuberculosis and Respiratory Diseases
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• 제69권3호
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• pp.177-183
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• 2010

Background: Smoking reduces pulmonary function and induces various lung diseases. Recently, the rate of emphysema detection has increased due to lung cancer screening with low-dose chest computed tomography (CT). The purpose of this study was to evaluate changes in lung function associated with emphysema in healthy smokers. Methods: One hundred and ninety one healthy smokers, who had undergone a low-dose chest CT (LDCT) scan as part of lung cancer screening and had revisited the health center after a median 23.9 months' time, were recruited into this study. The severity of emphysema was calculated by the direct observation of a radiologist and a pulmonologist indipendently. Longitudinal changes in lung function according to emphysema based on LDCT and type of smoker was analyzed. Results: Of the participants in this study, 25% of healthy smokers had emphysema, which was mild in severity, in older patients (p=0.003) and in heavy smokers (p<0.001). $FEV_1/FVC$ and FEF25-75% were decreased in current smokers with emphysema (p=0.001 and p=0.009, respectively) and without emphysema (p=0.001 and p=0.042). Although lung function was not decreased in ex-smokers without emphysema, $FEV_1/FVC$ and FEF25-75% were decreased in ex-smoker with emphysema (p=0.020 and p=0.010). Conclusion: Upon examination with LDCT, the prevalence of emphysema was higher in healthy smokers was than in non-smokers. Lung function was diminished in smokers with emphysema, in spite of former smoker.

• Molecules and Cells
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• 제38권4호
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• pp.373-379
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• 2015

Pyruvate kinase M2 isoform (PKM2), a rate-limiting enzyme in the final step of glycolysis, is known to be associated with the metabolic rewiring of cancer cells, and considered an important cancer therapeutic target. Herein, we report a novel PKM2 activator, PA-12, which was identified via the molecular docking-based virtual screening. We demonstrate that PA-12 stimulates the pyruvate kinase activity of recombinant PKM2 in vitro, with a half-maximal activity concentration of $4.92{\mu}M$, and effectively suppresses both anchorage-dependent and -independent growth of lung cancer cells in non-essential amino acid-depleted medium. In addition, PA-12 blocked the nuclear translocalization of PKM2 in lung cancer cells, resulting in the inhibition of hypoxia response element (HRE)-mediated reporter activity as well as hypoxia-inducible factor 1 (HIF-1) target gene expression, eventually leading to the suppression of cell viability under hypoxia. We also verified that the effects of PA-12 were dependent on PKM2 expression in cancer cells, demonstrating the specificity of PA-12 for PKM2 protein. Taken together, our data suggest that PA-12 is a novel and potent PKM2 activator that has therapeutic implications for lung cancer.

• Asian Pacific Journal of Cancer Prevention
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• 제16권15호
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• pp.6599-6603
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• 2015

Background: For the determination of creatine kinase (CK)-MB, the immunoinhibition method is utilized most commonly. However, the estimated CK-MB activity may be influenced by the presence of CK isoenzymes in some conditions like cancer. Thus, a CK-MB-to-total-CK ratio more than 1.0 could be found in such a situation. The study aimed to explore the relationship of cancer to high CK-MB-to-total-CK ratio. Materials and Methods: From January 2011 to December 2014, laboratory data on all CK-MB and total CK test requests were extracted at Far Eastern Memorial Hospital (88,415 requests). Patients with a CK-MB-to-total-CK ratio more than 1.0 were registered in this study. Clinical data including tumor location, tumor TNM stage and metastatic status were also collected. Results: A total of 846 patients were identified with a CK-MB-to-total-CK ratio more than 1.0. Of these, 339 (40.1%) were diagnosed with malignancies. The mean CK-MB-to-total-CK ratio was significantly higher in malignancy than in non-malignancy ($1.35{\pm}0.28$ vs $1.25{\pm}0.23$, p<0.001) groups. The most frequent malignancy with a CK-MB-to-total-CK ratio more than 1.0 was colorectal cancer ($1.42{\pm}0.28$, 16.5%, n=56), followed by lung cancer ($1.38{\pm}0.24$, 15.9%, n=54) and hepatocellular carcinoma (14.5%, n=49). Higher CK-MB-to-total-CK ratios in hematological malignancies ($1.44{\pm}0.41$)were also noted. Additionally, the CK-MB-to-total-CK ratio was markedly higher in advanced stage malignancy than in early stage ($1.37{\pm}0.26$ vs. $1.29{\pm}0.31$, p=0.014) and significantly higher in liver metastasis than in non-liver metastasis ($1.48{\pm}0.30$ vs. $1.30{\pm}0.21$, p<0.001). Conclusions: The CK-MB-to-total-CK ratio is an easily available indicator and could be clinically utilized as a primary screening tool for cancer. Higher ratio of CK-MB-to-total-CK was specifically associated with certain malignancies, like colorectal cancer, lung cancer and hepatocellular carcinoma, as well as some cancer-associated status factors such as advanced stage and liver metastasis.

• Journal of Preventive Medicine and Public Health
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• 제43권2호
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• pp.185-192
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• 2010

Objectives: We conducted a meta-analysis to investigate the relationship between low external doses of ionizing radiation exposure and the risk of cancer mortality among nuclear power plant workers. Methods: We searched MEDLINE using key words related to low dose and cancer risk. The selected articles were restricted to those written in English from 1990 to January 2009. We excluded those studies with no fit to the selection criteria and we included the cited references in published articles to minimize publication bias. Through this process, a total of 11 epidemiologic studies were finally included. A publication bias was tested for using Egger's test. The homogeneity test was performed before the integration of each of the standardized mortality ratios (SMRs) and the result proved that the studies were heterogeneous. Results: We found significant decreased deaths from all cancers (SMR = 0.75, 95% CI = 0.62 - 0.90), all cancers excluding leukemia, solid cancer, mouth and pharynx, esophagus, stomach, rectum, liver and gallbladder, pancreas, lung, prostate, lymphopoietic and hematopoitic cancer. The findings of this meta-analysis were similar with those of the 15 Country Collaborative Study conducted by the International Agency for Research on Cancer. A publication bias was found only for liver and gallbladder cancer (p = 0.015). Heterogeneity was observed for all cancers, all cancers excluding leukemia, solid cancer, esophagus, colon and lung cancer. Conclusions: Our findings of low mortality for stomach, rectum, liver and gallbladder cancers may explained by the health worker effect. Yet further studies are needed to clarify the low SMR of cancers, for which there is no useful screening tool, in nuclear power plant workers.

• Tuberculosis and Respiratory Diseases
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• 제87권2호
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• pp.134-144
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• 2024

Interstitial lung abnormalities (ILAs) are radiologic abnormalities found incidentally on chest computed tomography (CT) that can be show a wide range of diseases, from subclinical lung fibrosis to early pulmonary fibrosis including definitive usual interstitial pneumonia. To clear up confusion about ILA, the Fleischner society published a position paper on the definition, clinical symptoms, increased mortality, radiologic progression, and management of ILAs based on several Western cohorts and articles. Recently, studies on long-term outcome, risk factors, and quantification of ILA to address the confusion have been published in Asia. The incidence of ILA was 7% to 10% for Westerners, while the prevalence of ILA was about 4% for Asians. ILA is closely related to various respiratory symptoms or increased rate of treatment-related complication in lung cancer. There is little difference between Westerners and Asians regarding the clinical importance of ILA. Although the role of quantitative CT as a screening tool for ILA requires further validation and standardized imaging protocols, using a threshold of 5% in at least one zone demonstrated 67.6% sensitivity, 93.3% specificity, and 90.5% accuracy, and a 1.8% area threshold showed 100% sensitivity and 99% specificity in South Korea. Based on the position paper released by the Fleischner society, I would like to report how much ILA occurs in the Asian population, what the prognosis is, and review what management strategies should be pursued in the future.

• Tuberculosis and Respiratory Diseases
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• 제82권3호
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• pp.217-226
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• 2019

Background: Depression is a recognized complication of lung cancer underreported in developing countries such as Malaysia. Treating and identifying depression in cancer patients increases survival and quality of life. Our objectives are to study prevalence of depressive symptoms in newly diagnosed lung carcinoma, and examine the relationship of depressive symptoms with other influencing risk factors. Methods: A 2-year, cross sectional study February 2015-February 2017, was conducted at Hospital Tengku Ampuan Afzan, and Penang General Hospital. One hundred and three patients with newly diagnosed, biopsy confirmed primary lung carcinoma were recruited. Self-rated patient's identification sheet, validated Center for Epidemiologic Studies Depression (CES-D), and Dukes University Religion Index score from three different main languages were used. Results: Prevalence of current depressive symptoms (CES-D total score ${\geq}16$) is 37.9%. The result suggests prevalence of those at high risk of moderate to major depression, may need treatment. Multivariate analysis reveals those with good Eastern Cooperation Oncology Group factor (${\eta}2=0.24$, p<0.001) married (${\eta}2=0.14$, p<0.001) with intrinsic religiosity (IR) (${\eta}2=0.07$, p<0.02) are more resistant to depression. Conclusion: One in three of lung carcinoma patients, are at increased risk for depression. Clinicians should be aware that risk is highest in those with poor performance status, single, and with poor IR. We suggest routine screening of depression symptoms as it is feasible, to be performed during a regular clinic visit with immediate referral to psychiatrist when indicated.

• Asian Pacific Journal of Cancer Prevention
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• 제15권7호
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• pp.3057-3063
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• 2014

Background: Anaplastic lymphoma kinase (ALK) gene rearrangement in non-small cell lung cancer (NSCLC) has been intensively studied. The gold standard for ALK detection is FISH, but this is not routinely conducted in clinical practice, so that the IHC method has a role. The aim of this study was to identify the incidence of ALK rearrangement and risk or prognostic factors for ALK positivity using both of IHC and FISH methods. Materials and Methods: From January 2008 to December 2012, 267 completely resected NSCLC patients in Chiang Mai University Hospital were enrolled in this study. Clinical and pathological variables and outcomes of treatment were retrospectively reviewed. IHC and FISH were used to evaluate ALK rearrangement. Sensitivity and specificity of IHC were analyzed. Multivariable analysis was used to identify clinico-pathological correlations with positive results of IHC and clinical outcomes. Results: Twenty-two (8.2%) of 267 specimens were IHC-positive for ALK with intense cytoplasmic staining, whereas only 10 (3.8%) were FISH-positive. Sensitivity, specificity and the positive likelihood ratio with IHC were 80.0%, 94.9%, and 15.8 respectively. Age less than 55 years (RR 4.4, 95%CI 1.78-10.73, p value=0.001) and presence of visceral pleural invasion (VPI) (RR 2.9, 95%CI 1.21-6.78, p value =0.017) were identified as risk factors for ALK rearrangement with FISH. There were no statistically significant differences in other clinical and pathological variables. ALK rearrangement was not a prognostic factor for tumor recurrence or overall survival. Conclusions: The incidences of ALK positivity in completely resected NSCLCs in northern Thailand were 8.2% by IHC and 3.8% by FISH. IHC with mouse monoclonal, Ventana D5F3 antibody can be used as a screening tool before FISH method because of high specificity and high positive likelihood ratio. Age less than 55 years and VPI are risk factors for ALK positivity.

• Applied Biological Chemistry
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• 제49권1호
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• pp.21-24
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• 2006

6종의 인체 암(폐암, 피부암, 결장암, 자궁암, 선암 및 뇌암)과 그의 17가지 세포주들에 대한 리간드 화합물 3,6-bis(2'-pyridyl)pyridazine(1) 과 3,6-bi s(6'-methyl-2'-pyridyl)pyridazine(2) 그리고 그들의 전이금속(Ni(II), Cu(II) 및 Zn(II)) 착 화합물들 $(3{\sim}6)$ 세포독성을 각각 측정하였다. 그 결과, 특히 Cu(II) 착 화합물, bis-[3,6-bis-(6'-methyl-2'-pyridyl)pyridazine-$k^2N^2,N^3$]chlorocopper(II)perchlorate (4)는 뇌암(SNB-19)과 결장암(SW-62) 세포주에 대하여 제1세대 항암제인 Cis-platin보다 높은 세포독성을 나타내었다.

• Asian Pacific Journal of Cancer Prevention
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• 제13권7호
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• pp.3065-3071
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• 2012

Aim: The present investigation was to evaluate the effects of essential oils of Wedelia chinensis (Osbeck) on free radicals and in vivo antioxidant properties. Methods: Essential oils were extracted using hydro-distillation and compound analysis was performed by GC-MS analysis. Screening for inhibitory activity was conducted by DPPH and OH-scavenging assays. In addition an in vivo study was carried out in cell line implanted cancer bearing mice with assessment of levels of catalase, superoxide dismutase, glutathione peroxidase, lipid peroxidation, nitric oxide and reduced glutathione. Finally, lungs were dissected out for histopathology study of metastasis. Results: GC-MS analysis revealed the presence of carvocrol and trans-caryophyllene as the major compounds with 96% comparison with the Wilily and NBS libraries. The essential oil exhibited significant inhibition in DPPH free radical formation. Whereas reducing power and hydroxyl radical scavenging activity are dose dependent. When compared with the standard, it was found that the essential oil has more or less equal activity in scavenging free radicals produced. In the animal studies, the level of antioxidant enzymes catalase, superoxide dismutase and glutathione peroxidase, as well as glutathione, were found to be increased in treated groups whereas lipid peroxidation and nitric oxide were reduced. Histopathology report also shows that the essential oil has a significant combating effect against cancer development. Conclusion: In all the in vitro assays, a significant correlation existed between the concentrations of the essential oil and percentage inhibition of free radicals. The in vivo studies also has shown a very good antioxidant property for the essential oil during cancer development. From, these results the essential oil can be recommended for treating disease related to free radicals and to prevent cancer development.