scholarly journals RLIP76 Gene Variants are not Associated with Drug Response in Turkish Epilepsy Patients

2011 ◽  
Vol 14 (1) ◽  
pp. 25-30 ◽  
Author(s):  
E Manguoğlu ◽  
S Akdeniz ◽  
N Dündar ◽  
Ö Duman ◽  
B Aktekin ◽  
...  
Keyword(s):  
Drug Resistance ◽  
High Performance ◽  
Drug Response ◽  
Resistance Mechanism ◽  
Sequence Variants ◽  
Gene Variants ◽  
Sequencing Analysis ◽  
Transporter Protein ◽  
Epileptic Patients ◽  
Response Status

RLIP76Gene Variants are not Associated with Drug Response in Turkish Epilepsy PatientsApproximately 30% of epileptic patients remain untreated, in spite of trials with maximum tolerable doses of more than one drug. The RalA binding protein 1 (RALBP1/RLIP76), a multifunctional, anti-apoptotic, multidrug transporter protein, has been proposed as being responsible for the drug resistance mechanism in epilepsy. We have investigated polymorphic differences in the coding regions and exon-intron boundaries of theRLIP76gene, between 146 refractory and 155 non refractory epileptic patients in Turkey, using denaturing high performance liquid chromatography (HPLC) and sequencing analysis techniques. We have detected the following sequence variants: c.160-4G>A, c.187C>G, c.1562-38G>A, c.1670+107G>A, c.1670+93G>A, c.1670+96G>A, c.1670+100C>T, c.1670+130C>T, c.1670+131G>C, c.1670+140 G>C, and found no statistically significant correlation between allele frequencies and drug response status. We conclude that sequence variants of this gene are not involved in drug resistance in epilepsy.

scholarly journals Genome sequencing and transcriptome analysis of Geotrichum citri-aurantii on citrus reveal the potential pathogenic- and guazatine resistance-related genes

2019 ◽  
Author(s):  
Juan Zhao ◽  
DeYao Zhang ◽  
Zhe Wang ◽  
Zhonghuan Tian ◽  
Fan Yang ◽  
...  
Keyword(s):  
Drug Resistance ◽  
Genome Sequence ◽  
Genomic Sequence ◽  
Resistance Mechanism ◽  
Effective Control ◽  
Postharvest Disease ◽  
Economic Losses ◽  
Sequencing Analysis ◽  
Transporter Family ◽  
High Quality Genome

Abstract Background: Citrus grow in more than 100 countries and is one of the most produced fruit genus. Sour rot, caused by Geotrichum citri-aurantii , is a major postharvest disease of citrus，and it causes economic losses. In recent years, the disease had a rising trend year by year. In this study, the genome sequence of G. citri-aurantii and transcriptome sequence of pathogenic- and guazatine resistance were sequenced with a view to explore the potential pathogenic mechanism and drug resistance mechanism of G. citri-aurantii on citrus. Results: We sequenced a high-quality genome sequence of G. citri-aurantii by SMRT. This sequence encodes 6,783 predicted genes of the 28.1-Mb G. citri-aurantii genome. Approximately 5.43 Gb of clean data were obtained after Hi-C sequencing, and a 27.94-Mb genomic sequence was positioned to the 10 chromosome groups after Hi-C assembly , accounting for 99.43% of the previously measured G. citri-aurantii genome. In the process of studying pathogenic mechanisms, the content of polygalacturonase (PG) and polymethylgalacturonase (PMG) was considerably increased in the Newhall navel orange infected by G. citri-aurantii. Then, three polygalacturonase (PG) genes (EVM0005942, EVM0004416, EVM0002276) related to pathogenicity were identified and the expression level was significantly increased during the infection by quantitative RT-PCR. Additionally, G. citri-aurantii is only sensitive to the chemical fungicide guazatine. Massive guazatine use has led to evolution of the wild G. citri-aurantii in citrus-producing areas. Owing to its uniqueness, RNA sequencing analysis of guazatine-resistance showed that the guazatine-resistance of G. citri-aurantii is may related to two ABC transporter family genes, six MFS transporter family genes and two MATE transporter family genes. Conclusions: We found three polygalacturonase (PG) genes related to pathogenicity and ten genes related to guazatine-resistance from molecular level. Our research may provide novel insights into the effective control of this pathogen. Keywords: Geotrichum citri-aurantii , citrus, genome, pathogenicity, guazatine, drug resistance

scholarly journals CTR-DB, an omnibus for patient-derived gene expression signatures correlated with cancer drug response

2021 ◽  
Author(s):  
Zhongyang Liu ◽  
Jiale Liu ◽  
Xinyue Liu ◽  
Xun Wang ◽  
Qiaosheng Xie ◽  
...  
Keyword(s):  
Gene Expression ◽  
Drug Resistance ◽  
Drug Response ◽  
Biomarker Discovery ◽  
Characteristic Curve ◽  
Resistance Mechanism ◽  
Predictive Biomarker ◽  
Gene Signature ◽  
Functional Enrichment ◽  
Cancer Drug

Abstract To date, only some cancer patients can benefit from chemotherapy and targeted therapy. Drug resistance continues to be a major and challenging problem facing current cancer research. Rapidly accumulated patient-derived clinical transcriptomic data with cancer drug response bring opportunities for exploring molecular determinants of drug response, but meanwhile pose challenges for data management, integration, and reuse. Here we present the Cancer Treatment Response gene signature DataBase (CTR-DB, http://ctrdb.ncpsb.org.cn/), a unique database for basic and clinical researchers to access, integrate, and reuse clinical transcriptomes with cancer drug response. CTR-DB has collected and uniformly reprocessed 83 patient-derived pre-treatment transcriptomic source datasets with manually curated cancer drug response information, involving 28 histological cancer types, 123 drugs, and 5139 patient samples. These data are browsable, searchable, and downloadable. Moreover, CTR-DB supports single-dataset exploration (including differential gene expression, receiver operating characteristic curve, functional enrichment, sensitizing drug search, and tumor microenvironment analyses), and multiple-dataset combination and comparison, as well as biomarker validation function, which provide insights into the drug resistance mechanism, predictive biomarker discovery and validation, drug combination, and resistance mechanism heterogeneity.

scholarly journals Clinical Identification of Dysregulated Circulating microRNAs and Their Implication in Drug Response in Triple Negative Breast Cancer (TNBC) by Target Gene Network and Meta-Analysis

Genes ◽  
2021 ◽  
Vol 12 (4) ◽  
pp. 549
Author(s):  
Amal Qattan ◽  
Taher Al-Tweigeri ◽  
Wafa Alkhayal ◽  
Kausar Suleman ◽  
Asma Tulbah ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Drug Resistance ◽  
Triple Negative Breast Cancer ◽  
Drug Response ◽  
Triple Negative ◽  
Meta Analysis ◽  
Integrated Analysis ◽  
Circulating Mirnas ◽  
Persistent Problem ◽  
Network Analyses

Resistance to therapy is a persistent problem that leads to mortality in breast cancer, particularly triple-negative breast cancer (TNBC). MiRNAs have become a focus of investigation as tissue-specific regulators of gene networks related to drug resistance. Circulating miRNAs are readily accessible non-invasive potential biomarkers for TNBC diagnosis, prognosis, and drug-response. Our aim was to use systems biology, meta-analysis, and network approaches to delineate the drug resistance pathways and clinical outcomes associated with circulating miRNAs in TNBC patients. MiRNA expression analysis was used to investigate differentially regulated circulating miRNAs in TNBC patients, and integrated pathway regulation, gene ontology, and pharmacogenomic network analyses were used to identify target genes, miRNAs, and drug interaction networks. Herein, we identified significant differentially expressed circulating miRNAs in TNBC patients (miR-19a/b-3p, miR-25-3p, miR-22-3p, miR-210-3p, miR-93-5p, and miR-199a-3p) that regulate several molecular pathways (PAM (PI3K/Akt/mTOR), HIF-1, TNF, FoxO, Wnt, and JAK/STAT, PD-1/PD-L1 pathways and EGFR tyrosine kinase inhibitor resistance (TKIs)) involved in drug resistance. Through meta-analysis, we demonstrated an association of upregulated miR-93, miR-210, miR-19a, and miR-19b with poor overall survival outcomes in TNBC patients. These results identify miRNA-regulated mechanisms of drug resistance and potential targets for combination with chemotherapy to overcome drug resistance in TNBC. We demonstrate that integrated analysis of multi-dimensional data can unravel mechanisms of drug-resistance related to circulating miRNAs, particularly in TNBC. These circulating miRNAs may be useful as markers of drug response and resistance in the guidance of personalized medicine for TNBC.

scholarly journals Effect of Allium senescens Extract on Sorafenib Resistance in Hepatocarcinoma Cells

2021 ◽  
Vol 11 (8) ◽  
pp. 3696
Author(s):  
Sohyeon Park ◽  
Yoonjin Park ◽  
Heejong Shin ◽  
Boyong Kim ◽  
Seunggwan Lee
Keyword(s):  
Drug Resistance ◽  
Hepg2 Cells ◽  
High Performance ◽  
Quantitative Polymerase Chain Reaction ◽  
Mitochondrial Apoptosis ◽  
Coumaric Acid ◽  
Allium Species ◽  
Hepatocarcinoma Cells ◽  
Polymerase Chain ◽  
Resistant Cells

Although Allium species are involved in bioactivity, to the best of our knowledge, there is no research on the effects of Allium senescens on drug resistance in hepatocarcinoma. Ultra-high performance liquid chromatography was used to determine the concentration of several bioactive compounds in A. senescens extract; flow cytometry, reverse transcription–quantitative polymerase chain reaction, and siRNA-mediated knockdown to estimate the levels of different markers in HepG2 cells. The quantity of p-coumaric acid in the extract was 4.7291 ± 0.06 μg/mL, and the protein of relevant evolutionary and lymphoid interest (PRELI) in the resistant cells decreased 2.1 times in the presence of p-coumaric acid. The resistant cells strongly downregulated the efflux transporters (ABCB1, ABCC2, and ABCG2) when exposed to the extract or p-coumaric acid and when PRELI was knocked down, in contrast to the influx proteins (OCT-1). Additionally, the extract induced mitochondrial apoptosis and suppressed autophagy. Consequently, the extract and p-coumaric acid attenuated drug resistance of HepG2 cells through the downregulation of PRELI, a key protein associated with the modulation of drug transporter expression, the activation of autophagy, and mitochondrial apoptosis. Our results indicate that A. senescens extract is beneficial in protecting cancer cells against drug resistance and sustaining the efficacy of sorafenib against liver cancer.

scholarly journals A Novel Multidrug-Resistant Cell Line from an Italian Intrahepatic Cholangiocarcinoma Patient

Cancers ◽  
2021 ◽  
Vol 13 (9) ◽  
pp. 2051
Author(s):  
Caterina Peraldo-Neia ◽  
Annamaria Massa ◽  
Francesca Vita ◽  
Marco Basiricò ◽  
Chiara Raggi ◽  
...  
Keyword(s):  
Drug Resistance ◽  
Cell Line ◽  
Intrahepatic Cholangiocarcinoma ◽  
Biological Behavior ◽  
Population Doubling ◽  
Sequencing Analysis ◽  
Tumor Type ◽  
Clinical Issue ◽  
Mesenchymal Transition

Chemotherapy resistance is a relevant clinical issue in tumor treatment, in particular in biliary tract carcinoma (BTC), for which there are no effective therapies, neither in the first nor in the second line. The development of chemoresistant cell lines as experimental models to investigate the mechanisms of resistance and identify alternative druggable pathways is mandatory. In BTC, in which genetics and biological behavior depend on the etiology, ethnicity, and anatomical site of origin, the creation of models that better recapitulate these characteristics is even more crucial. Here we have established and characterized an intrahepatic cholangiocarcinoma (iCCA) cell line derived from an Italian patient, called 82.3. Cells were isolated from a patient-derived xenograft (PDX) and, after establishment, immunophenotypic, biological, genetic, molecular characteristics, and tumorigenicity in vivo in NOD/SCID mice were investigated. 82.3 cells exhibited epithelial morphology and cell markers (EPCAM, CK7, and CK19); they also expressed different cancer stem markers (CD44, CD133, CD49b, CD24, Stro1, PAX6, FOXA2, OCT3/4), α–fetoprotein and under anchorage-independent and serum-free conditions were capable of originating cholangiospheres. The population doubling time was approximately 53 h. In vitro, they demonstrated a poor ability to migrate; in vivo, 82.3 cells retained their tumorigenicity, with a long latency period (16 weeks). Genetic identity using DNA fingerprinting analysis revealed 16 different loci, and the cell line was characterized by a complex hyperdiploid karyotype. Furthermore, 82.3 cells showed cross-resistance to gemcitabine, 5-fluorouracil, carboplatin, and oxaliplatin; in fact, their genetic profile showed that 60% of genes (n = 168), specific for drug resistance and related to the epithelial-mesenchymal transition, were deregulated in 82.3 cells compared to a control iCCA cell line sensitive to chemotherapeutics. RNA sequencing analysis revealed the enrichment for genes associated with epithelial to mesenchymal transition (EMT), vasculature development, and extracellular matrix (ECM) remodeling, underlining an aggressive phenotype. In conclusion, we have created a new iCCA cell line of Caucasian origin: this could be exploited as a preclinical model to study drug resistance mechanisms and to identify alternative therapies to improve the prognosis of this tumor type.

scholarly journals Molecular modeling study on the drug resistance mechanism of NS5B polymerase to TMC647055

2016 ◽  
Vol 94 (2) ◽  
pp. 147-158 ◽  
Author(s):  
Huiqun Wang ◽  
Wei Cui ◽  
Chenchen Guo ◽  
Bo-Zhen Chen ◽  
Mingjuan Ji
Keyword(s):  
Drug Resistance ◽  
Free Energy ◽  
Rational Design ◽  
Binding Free Energy ◽  
Resistance Mechanism ◽  
Free Energy Calculations ◽  
Side Chain ◽  
Free Energy Decomposition ◽  
Hcv Ns5b ◽  
Ns5b Polymerase

NS5B polymerase plays an important role in viral replication machinery. TMC647055 (TMC) is a novel and potent non-nucleoside inhibitor of the HCV NS5B polymerase. However, mutations that result in drug resistance to TMC have been reported. In this study, we used molecular dynamics (MD) simulations, binding free energy calculations, and free energy decomposition to investigate the drug resistance mechanism of HCV to TMC resulting from L392I, P495T, P495S, and P495L mutations in NS5B polymerase. From the calculated results we determined that the decrease in the binding affinity between TMC and NS5BL392I polymerase is mainly caused by the extra methyl group at the CB atom of Ile. The polarity of the side-chain of residue 495 has no distinct influence on residue 495 binding with TMC, whereas the smaller size of the side-chain of residue 495 causes a substantial decrease in the van der Walls interaction between TMC and residue 495. Moreover, the longer length of the side-chain of residue 495 has a significant effect on the electrostatic interaction between TMC and Arg-503. Finally, we performed the same calculations and detailed analysis on other 3 mutations (L392V, P495V, and P495I). The results further confirmed our conclusions. The computational results not only reveal the drug resistance mechanism between TMC647055 and NS5B polymerase, but also provide valuable information for the rational design of more potent non-nucleoside inhibitors targeting HCV NS5B polymerase.

Investigation of the stab resistance mechanism and performance of uncoated and SiO2 coated high-performance aramid fabrics

2021 ◽  
pp. 1-16
Author(s):  
Muhammad Usman Javaid ◽  
Abdul Jabbar ◽  
Muhammad Irfan ◽  
Zafar Javed ◽  
Muhammad Salman Naeem ◽  
...  
Keyword(s):  
High Performance ◽  
Resistance Mechanism ◽  
Stab Resistance ◽  
And Performance ◽  
Aramid Fabrics

scholarly journals Cell type–dependent bimodal p53 activation engenders a dynamic mechanism of chemoresistance

2018 ◽  
Vol 4 (12) ◽  
pp. eaat5077 ◽  
Author(s):  
Ruizhen Yang ◽  
Bo Huang ◽  
Yanting Zhu ◽  
Yang Li ◽  
Feng Liu ◽  
...  
Keyword(s):  
Drug Resistance ◽  
Cellular Response ◽  
Resistance Mechanism ◽  
Genetic Mutation ◽  
Single Cell Imaging ◽  
Regulatory Module ◽  
Response To Chemotherapy ◽  
Activation Dynamics ◽  
Inhibitory Strength ◽  
P53 Activation

Studies of drug resistance mostly characterize genetic mutation, and we know much less about phenotypic mechanisms of drug resistance, especially at a quantitative level. p53 is an important mediator of cellular response to chemotherapy, but even p53 wild-type cells vary in drug sensitivity for unclear reasons. Here, we elucidated a new resistance mechanism to a DNA-damaging chemotherapeutic through bimodal modulation of p53 activation dynamics. By combining single-cell imaging with computational modeling, we characterized a four-component regulatory module, which generates bimodal p53 dynamics through coupled feed-forward and feedback, and found that the inhibitory strength between ATM and Mdm2 determined the differential modular output between drug-sensitive and drug-resistant cancer cell lines. We further showed that the combinatorial inhibition of Mdm2 and Wip1 was an effective strategy to alter p53 dynamics in resistant cancer cells and sensitize their apoptotic response. Our results point to p53 pulsing as a potentially druggable mechanism that mediates chemoresistance.

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