• Journal of Yeungnam Medical Science
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• 제28권1호
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• pp.13-19
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• 2011

The emergence of antibiotic-resistant pathogens is a Serious clinical problem in the treatment of infectious diseases that increase mortality, morbidity, hospitalization length, and the cost of healthcare. In particular, $Streptococcus$ $pneumoniae$ is a major etiologic pathogen of pneumonia, sinusitis, otitis media, and meningitis. As the definition of penicillin resistance to $S.$ $pneumoniae$ was recently changed, macrolide-resistant $S.$ $pneumoniae$ is a major resistant pathogen in the community. Infections caused by antibiotic-resistant strains are associated with incorrect use of antibiotics and critical clinical outcomes. For the appropriate use of antibiotics to treat infections, physicians always should have up-to-date information on the current epidemiologic status of antibiotic resistance for common pathogens and their susceptibility to antimicrobials. Appropriate selection of antimicrobials, strict control of infection, vaccination, and development of a feasible national policy of infection control are important strategies for the control of antimicrobial resistance. This review article focuses on the current status of antibiotic-resistant $S.$ $pneumoniae$ in community-acquired pneumonia in Korea.

• Asian Pacific Journal of Cancer Prevention
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• 제16권7호
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• pp.2793-2800
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• 2015

In molecular-targeted cancer therapy, acquired resistance to gemcitabine is a major clinical problem that reduces its effectiveness, resulting in recurrence and metastasis of cancers. In spite of great efforts to reveal the overall mechanism of acquired gemcitabine resistance, no definitive genetic factors have been identified that are absolutely responsible for the resistance process. Therefore, we performed a cross-platform meta-analysis of three publically available microarray datasets for cancer cell lines with acquired gemcitabine resistance, using the R-based RankProd algorithm, and were able to identify a total of 158 differentially expressed genes (DEGs; 76 up- and 82 down-regulated) that are potentially involved in acquired resistance to gemcitabine. Indeed, the top 20 up- and down-regulated DEGs are largely associated with a common process of carcinogenesis in many cells. For the top 50 up- and down-regulated DEGs, we conducted integrated analyses of a gene regulatory network, a gene co-expression network, and a protein-protein interaction network. The identified DEGs were functionally enriched via Gene Ontology hierarchy and Kyoto Encyclopedia of Genes and Genomes pathway analyses. By systemic combinational analysis of the three molecular networks, we could condense the total number of DEGs to final seven genes. Notably, GJA1, LEF1, and CCND2 were contained within the lists of the top 20 up- or down-regulated DEGs. Our study represents a comprehensive overview of the gene expression patterns associated with acquired gemcitabine resistance and theoretical support for further clinical therapeutic studies.

• BMB Reports
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• 제51권12호
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• pp.660-665
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• 2018

Human epidermal growth factor receptor 2 (HER2) inhibitors, such as trastuzumab and lapatinib are used to treat HER2-positive breast and gastric cancers. However, as with other targeted therapies, intrinsic or acquired resistance to HER2 inhibitors presents unresolved therapeutic problems for HER2-positive gastric cancer. The present study describes investigations with AUY922, a heat shock protein 90 (HSP90) inhibitor, in primary lapatinib-resistant (ESO26 and OE33) and lapatinib-sensitive gastric cancer cells (OE19, N87, and SNU-216) harboring HER2 amplification/over-expression. In order to investigate whether AUY922 could overcome intrinsic and acquired resistance to HER2 inhibitors in HER2-positive gastric cancer, we generated lapatinib-resistant gastric cancer cell lines (OE19/LR and N87/LR) by continuous exposure to lapatinib in vitro. We found that activation of HER2 and protein kinase B (AKT) were key factors in inducing intrinsic and acquired lapatinib-resistant gastric cancer cell lines, and that AUY922 effectively suppressed activation of both HER2 and AKT in acquired lapatinib-resistant gastric cancer cell lines. In conclusion, AUY922 showed a synergistic anti-cancer effect with lapatinib and sensitized gastric cancer cells with intrinsic resistance to lapatinib. Dual inhibition of the HSP90 and HER2 signaling pathways could represent a potent therapeutic strategy to treat HER2-positive gastric cancer with intrinsic and acquired resistance to lapatinib.

• Biomolecules & Therapeutics
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• 제12권2호
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• pp.85-91
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• 2004

In all attempt to elucidate the role of apoptosis in drug resistance, cisplatin-resistant human chronic myelogenous leukemia (CML) K562 cells (K562/CDDP) were established and compared with drug sensitive parent cells (K562) in the induction of apoptosis. K562/CDDP cells were 5-fold more resistant to cisplatin compared to K562 cells. In addition, K562/CDDP cells were significantly more resistant to apoptois as judged by DNA fragmentation and DAPI staining. K562/CDDP cells exhibited decreased proleolytic activity of caspase-3 and this was further demonstrated by decreased cleavage of its substrate poly (ADP-ribose) polymerase (PARR- Western blot analysis showed that K562/CDDP cells had longer sustained levels of BCL-$X_L$ whereas no difference was noted in the level of Bcl-2. the translocation of Bax to mitochondria was significantly delayed in K562/CDDP cells. These results suggest that the reduced translocation of Bax and the sustained expression of BCL-$X_L$ may cause resistance to apoptosis through prevention of mitochondria release of cytochrome c, which subsequently induces reduction of caspase-3 activity and that this response is partly responsible for the acquired resistance to cisplatin ill K562 cells.

• Biotechnology and Bioprocess Engineering:BBE
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• 제6권4호
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• pp.252-263
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• 2001

Nematode infections compromise human health and reduce agricultural productivtiy. Experiments that exploit the powerful molecular genetics of the free-living nematode Caenorhabdl - elegans have contributed to our understanding of how the major classes of anthelmintic nema-tocides kill worms and how worms might evolve resistance to these drugs In C. elegans, as in parasites, benzimidixoles interfere with microtubule polyumerization the imidazothiazoles/tetra-hydropyrimidines activate nicotinic acetylcholine receptors, and the macrocyclic la ctones activate qlutamate-gate chloride chanels. Mutant alleles of genes that encode drug targes often confer resistance in C. elegans. Preliminary evidence suggests that alleles of homologous genes in parasites will, in many cases, also play a role in resistance. Thus information acquired from C. elegans can be usefully applied to understand the mechanisms of drug sensitivity and the genetics of resis-tance in parasites.

• Genomics & Informatics
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• 제21권2호
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• pp.20.1-20.10
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• 2023

Aromatase inhibitors (AI) are drugs that are widely used in treating estrogen receptor (ER)-positive breast cancer patients. Drug resistance is a major obstacle to aromatase inhibition therapy. There are diverse reasons behind acquired AI resistance. This study aims at identifying the plausible cause of acquired AI resistance in patients administered with non-steroidal AIs (anastrozole and letrozole). We used genomic, transcriptomic, epigenetic, and mutation data of breast invasive carcinoma from The Cancer Genomic Atlas database. The data was then separated into sensitive and resistant sets based on patients' responsiveness to the non-steroidal AIs. A sensitive set of 150 patients and a resistant set of 172 patients were included for the study. These data were collectively analyzed to probe into the factors that might be responsible for AI resistance. We identified 17 differentially regulated genes (DEGs) among the two groups. Then, methylation, mutation, miRNA, copy number variation, and pathway analyses were performed for these DEGs. The top mutated genes (FGFR3, CDKN2A, RNF208, MAPK4, MAPK15, HSD3B1, CRYBB2, CDC20B, TP53TG5, and MAPK8IP3) were predicted. We also identified a key miRNA - hsa-mir-1264 regulating the expression of CDC20B. Pathway analysis revealed HSD3B1 to be involved in estrogen biosynthesis. This study reveals the involvement of key genes that might be associated with the development of AI resistance in ER-positive breast cancers and hence may act as a potential prognostic and diagnostic biomarker for these patients.

• Archives of Pharmacal Research
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• 제29권11호
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• pp.1018-1023
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• 2006

Chemoresistance remains the major obstacle to successful therapy of cancer. In order to understand the mechanism of multidrug resistance (MDR) that is frequently observed in lung cancer patients, here we studied the contribution of MDR-related proteins by establishing lung cancer cell lines with acquired resistance against etoposide. We found that human H460 lung cancer cells responded to etoposide more sensitively than A549 cells. Among MDR-related proteins, the expression of p-glycoprotein (Pgp) and lung resistance protein (LRP) were much higher in A549 cells compared with that in H460 cells. When we established H460-R1 and -R2 cell lines by progressive exposure of H460 cells to increasing doses of etoposide, the response against etopbside as well as doxorubicin was greatly reduced in R1 and R2 cells, suggesting MDR induction. Induction of MDR was not accompanied by a decrease in the intracellular accumulation of etoposide and the expression of MDR-related proteins that function as drug efflux pumps such as Pgp and MRP1 was not changed. We found that the acquired resistance paralleled an increased expression of LRP in H460 cells. Taken together, our data suggest the implicative role of LRP in mediating MDR in lung cancer.

• Biomolecules & Therapeutics
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• 제27권3호
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• pp.302-310
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• 2019

Melanoma cells have been shown to respond to BRAF inhibitors; however, intrinsic and acquired resistance limits their clinical application. In this study, we performed RNA-Seq analysis with BRAF inhibitor-sensitive (A375P) and -resistant (A375P/Mdr with acquired resistance and SK-MEL-2 with intrinsic resistance) melanoma cell lines, to reveal the genes and pathways potentially involved in intrinsic and acquired resistance to BRAF inhibitors. A total of 546 differentially expressed genes (DEGs), including 239 up-regulated and 307 down-regulated genes, were identified in both intrinsic and acquired resistant cells. Gene ontology (GO) analysis revealed that the top 10 biological processes associated with these genes included angiogenesis, immune response, cell adhesion, antigen processing and presentation, extracellular matrix organization, osteoblast differentiation, collagen catabolic process, viral entry into host cell, cell migration, and positive regulation of protein kinase B signaling. In addition, using the PAN-THER GO classification system, we showed that the highest enriched GOs targeted by the 546 DEGs were responses to cellular processes (ontology: biological process), binding (ontology: molecular function), and cell subcellular localization (ontology: cellular component). Ingenuity pathway analysis (IPA) network analysis showed a network that was common to two BRAF inhibitorresistant cells. Taken together, the present study may provide a useful platform to further reveal biological processes associated with BRAF inhibitor resistance, and present areas for therapeutic tool development to overcome BRAF inhibitor resistance.

• Asian Pacific Journal of Cancer Prevention
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• 제16권10호
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• pp.4147-4156
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• 2015

Lung cancer is a serious health problem and leading cause of death worldwide due to its high incidence and mortality. More than 80% of lung cancers feature a non-small cell histology. Over few decades, systemic chemotherapy and surgery are the only treatment options in this type of tumor but due to their limited efficacy and overall poor survival of patients, there is an urge to develop newer therapeutic strategies which circumvent the problems. Enhanced knowledge of translational science and molecular biology have revealed that lung tumors carry diverse driver gene mutations and adopt different intracellular pathways leading to carcinogenesis. Hence, the development of targeted agents against molecular subgroups harboring critical mutations is an attractive approach for therapeutic treatment. Targeted therapies are clearly more preferred nowadays over systemic therapies because they target tumor specific molecules resulting with enhanced activity and reduced toxicity to normal tissues. Thus, this review encompasses comprehensive updates on targeted therapies for the driver mutations in non-small cell lung cancer (NSCLC) and the potential challenges of acquired drug resistance faced i n the field of targeted therapy along with the imminent newer treatment modalities against lung cancer.

• Journal of Microbiology and Biotechnology
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• 제31권5호
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• pp.733-739
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• 2021

Acinetobacter strains are widely present in the environment. Some antimicrobial-resistant strains of this genus have been implicated in infections acquired in hospitals. Genetic similarities have been reported between Acinetobacter strains in nosocomial infections and those isolated from foods. However, the antimicrobial resistance of Acinetobacter strains in foods, such as meat, remains unclear. This study initially aimed to isolate Campylobacter strains; instead, strains of the genus Acinetobacter were isolated from meat products, and their antimicrobial resistance was investigated. In total, 58 Acinetobacter strains were isolated from 381 meat samples. Of these, 32 strains (38.6%) were from beef, 22 (26.5%) from pork, and 4 (4.8%) from duck meat. Antimicrobial susceptibility tests revealed that 12 strains were resistant to more than one antimicrobial agent, whereas two strains were multidrug-resistant; both strains were resistant to colistin. Cephalosporin antimicrobials showed high minimal inhibitory concentration against Acinetobacter strains. Resfinder analysis showed that one colistin-resistant strain carried mcr-4.3; this plasmid type was not confirmed, even when analyzed with PlasmidFinder. Analysis of the contig harboring mcr-4.3 using BLAST confirmed that this contig was related to mcr-4.3 of Acinetobacter baumannii. The increase in antimicrobial resistance in food production environments increases the resistance rate of Acinetobacter strains present in meat, inhibits the isolation of Campylobacter strains, and acts as a medium for the transmission of antimicrobial resistance in the environment. Therefore, further investigations are warranted to prevent the spread of antimicrobial resistance in food products.