ERCC1 and RRM1 but not EGFR gene expression is predictive of shorter survival in advanced non-small cell lung cancer (NSCLC)

2006 ◽  
Vol 24 (18_suppl) ◽  
pp. 10030-10030
Author(s):  
G. Selvaggi ◽  
P. Ceppi ◽  
M. Volante ◽  
S. Saviozzi ◽  
S. Novello ◽  
...  
Keyword(s):  
Gene Expression ◽  
Excision Repair ◽  
Growth Factor Receptor ◽  
Needle Aspiration ◽  
Differential Sensitivity ◽  
Mrna Levels ◽  
Female Ratio ◽  
Expression Levels ◽  
Egfr Expression ◽  
Formalin Fixed Paraffin Embedded

10030 Background: Pivotal studies indicate a role of excision repair cross-complementation 1 (ERCC1) and ribonucleotide reductase M1 (RRM1) in conferring a differential sensitivity to cytotoxic chemotherapy and epidermal growth factor receptor (EGFR) has been recently deeply investigated in NSCLC. Methods: We retrospectively collected 70 formalin-fixed paraffin-embedded (FFPE) bronchoscopic/fine needle aspiration biopsies of NSCLC to investigate the expression levels of ERCC1, RRM1 and EGFR by Real-Time PCR (Lord R et al. Clin Cancer Research 2002, 8:2286–91). Results were correlated with survival using the Kaplan-Meier method. Results: Sixty-one (87%) specimens were successfully amplified. Median age was 62 years (range 26–75), male/ female ratio 44/17, stage III/IV 20/41; 43 patients received cisplatin-based chemotherapy; overall median survival (MS) was 13.3 months over a median follow-up time of 45 months. ERCC1 expression level ranged from 0.70 to 15.12, RRM1 0.60–17.82. By adopting cut-off values according to median expression levels, we found a strong correlation between ERCC1 and RRM1 mRNA levels (r=0.410; p<0.001). MS in patients with low ERCC1 was significantly longer (16.9 vs 11.3 months, p<0.006) as well as in patients with low RRM1 (13.9 vs 10.9 months, p<0.03). Concomitant high expression levels of ERCC1 and RRM1 (n=26) are predictive of a worse outcome (13.9 vs 10.9 months, p<0.05). Among patients treated with cisplatin-based regimens, low ERCC1 levels were also predictive of a significantly longer MS (23.0 vs 11.6 months, p<0.002). A lower median ERCC1 level (3.2 vs 4.7) and a correlation with a better outcome were also observed in females vs males. No correlation between gene expression levels and histology was reported. No significant correlation between EGFR expression levels (range 0.5–85.8) and survival was found, even when different cut-off values were tested. Conclusions: This retrospective study further validates ERCC1 and RRM1 as good candidates genes to customize chemotherapy. Prospective studies based on the selection of patients according to genes expression levels are a research priority in early and advanced stages of NSCLC. [Table: see text]

Molecular profiling in patients (pts) with upper gastrointestinal (UGI) cancers correlated with clinical outcome

2009 ◽  
Vol 27 (15_suppl) ◽  
pp. e22042-e22042
Author(s):  
N. Virk ◽  
D. Yang ◽  
H. J. Lenz ◽  
A. B. El-Khoueiry ◽  
K. D. Danenberg ◽  
...  
Keyword(s):  
Gene Expression ◽  
Colon Cancer ◽  
Clinical Outcome ◽  
Excision Repair ◽  
Statistical Significance ◽  
Molecular Profiling ◽  
Cytotoxic Agents ◽  
Mrna Levels ◽  
Expression Levels ◽  
Gene Expression Levels

e22042 Background: Recent efforts have expanded our understanding of the molecular pathogenesis of UGI cancers and how oncogenes and tumor suppressor genes play a role in both carcinogenic and metastatic processes. These markers may serve as prognostic and/or predictive factors for recurrence following resection and resistance to radiotherapy and chemotherapy. Gene expression levels of thymidylate synthase (TS), thymidylate phosphorylase (TP), epidermal growth factor receptor (EGFR) and excision repair cross complementing (ERCC-1) have been shown to be associated with outcomes in lung, gastric and colon cancer. We evaluated TS, ERCC-1, EGFR and TP gene expression levels in patients with UGI cancers. Methods: This was a retrospective study of 80 pts with UGI cancers evaluated at USC who underwent molecular profiling. The primary objective was to determine a correlation between TS, TP, ERCC1 and EGFR and correlate with clinical outcome. Characteristics of these 80 pts: (16 females, 64 males ); median age 61 years (range 34–85); tumor types evaluated - 32 (40%) esophageal, 24(30%) gastric, 24(30%) GE junction; stages- 53 % IV, 21% III, 12% II, 2% I were evaluated for intratumoral gene expression of TS, TP, ERCC-1, & EGFR by real time quantitative PCR using Taqman technology from microdisected paraffin-embedded tumor sections. Results: High TS expression was associated with shorter OS (12.8 months vs. 23.7 months p=0.036). A significant correlation was found between TP & ERCC-1 (p=0.0078, r=0.37); TP & TS (p=0.0128, r=0.35); TP & EGFR (p=0.0065, r=0.39); TS & ERCC-1 (p=0.0004, r=0.39); ERCC-1 & EGFR (p=0.025, r=0.30). No statistically significant relationship was found between TS & EGFR (p=0.06,r=0.25). There was no correlation of ERCC-1, TP, & EGFR with OS that reached statistical significance. Conclusions: TS mRNA levels were shown to be associated with OS in UGI tumors, consistent with data reported in colon cancer. TS gene expression was significantly associated with expression levels of ERCC-1. In addition, ERCC1 was associated with EGFR. These data show for the first time that molecular pathways of cytotoxic agents are linked to the EGFR pathway suggesting that sensitivity to fluoropyrimidines, oxaliplatin, and EGFR inhibitors may be associated. No significant financial relationships to disclose.

scholarly journals Methylobacterium oryzae Influences Isoepoxydon Dehydrogenase Gene Expression and Patulin Production by Penicillium expansum

Water ◽  
2021 ◽  
Vol 13 (10) ◽  
pp. 1427
Author(s):  
Tiago Barros Afonso ◽  
Lúcia Chaves Simões ◽  
Nelson Lima
Keyword(s):  
Gene Expression ◽  
Distribution Systems ◽  
Water Distribution ◽  
Penicillium Expansum ◽  
Transcriptional Level ◽  
Positive Trend ◽  
Mrna Levels ◽  
Expression Levels ◽  
Production Values ◽  
Methylobacterium Oryzae

Biofilms can be considered the main source of microorganisms in drinking water distribution systems (DWDS). The ecology of a biofilm is dependent on a variety of factors, including the presence of microbial metabolites excreted by its inhabitants. This study reports the effect of the Gram-negative bacteria Methylobacterium oryzae on the idh gene expression levels and patulin production of Penicillium expansum mature biofilms. For this purpose, a RT-qPCR method to quantify idh mRNA levels was applied. In addition, the idh expression levels were compared with the patulin production. The results obtained revealed that the effect of the bacterium on pre-established P. expansum biofilms is dependent on the time of interaction. More mature P. expansum biofilms appear to be more resistant to the inhibitory effect that M. oryzae causes towards idh gene expression and patulin production. A positive trend was observed between the idh expression and patulin production values. The results indicate that M. oryzae affects patulin production by acting at the transcriptional level of the idh gene.

scholarly journals Gene Expression of Nucleic Acid-Sensing Pattern Recognition Receptors in Children Hospitalized for Respiratory Syncytial Virus-Associated Acute Bronchiolitis

2009 ◽  
Vol 16 (6) ◽  
pp. 816-823 ◽  
Author(s):  
Carolina Scagnolari ◽  
Fabio Midulla ◽  
Alessandra Pierangeli ◽  
Corrado Moretti ◽  
Enea Bonci ◽  
...  
Keyword(s):  
Gene Expression ◽  
Pattern Recognition ◽  
Viral Load ◽  
Respiratory Syncytial Virus ◽  
Pattern Recognition Receptors ◽  
Mrna Levels ◽  
Acute Bronchiolitis ◽  
Expression Levels ◽  
Rsv Infection ◽  
Syncytial Virus

ABSTRACT Given the critical role of pattern recognition receptors (PRRs) in acid nucleic recognition in the initiation of innate immunity and the orchestration of adaptive immunity, the aim of this study was to determine whether any heterogeneity of PRR expression in the airway tracts of infants with respiratory syncytial virus (RSV) infection might explain the broad clinical spectrum of RSV-associated bronchiolitis in infants. For this purpose, the levels of melanoma differentiation-associated protein-5 (MDA-5), retinoic acid inducible gene-1 (RIG-1), and Toll-like receptor 3 (TLR-3), TLR-7, TLR-8, and TLR-9 mRNAs were evaluated, using TaqMan quantitative reverse transcription-PCR, in cells from nasopharyngeal washes collected from 157 infants suffering from acute bronchiolitis whether or not they were associated with respiratory viruses. High interindividual variability was observed in both virus-positive and -negative infants; however, the relative gene expression levels of MDA-5, RIG-1, TLR-7, and TLR-8 were significantly higher in the virus-infected group, whereas the expression levels of TLR-3 and TLR-9 were not significantly different. The differences in the gene expression of MDA-5, RIG-1, TLR-7, and TLR-8 were more evident in infants with RSV infection than in those with bocavirus or rhinovirus infection. In RSV-infected infants, PRR-mRNA levels also were analyzed in relation to interferon protein levels, viral load, clinical severity, days of hospitalization, age, and body weight. A significant positive correlation was observed only between RSV viral load and RIG-1 mRNA levels. These findings provide the first direct evidence that, in infants with respiratory virus-associated bronchiolitis, especially RSV, there are substantial changes in PRR gene expression; this likely is an important determinant of the clinical outcome of bronchiolitis.

scholarly journals Heterogeneous recruitment abilities to RNA polymerases generate nonlinear scaling of gene expression with cell volume

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Qirun Wang ◽  
Jie Lin
Keyword(s):  
Gene Expression ◽  
Cell Volume ◽  
Direct Consequence ◽  
Rna Polymerases ◽  
Mrna Levels ◽  
Expression Levels ◽  
Promoter Sequences ◽  
Biophysical Mechanism ◽  
Expression Model ◽  
Cycle Regulation

AbstractWhile most genes’ expression levels are proportional to cell volumes, some genes exhibit nonlinear scaling between their expression levels and cell volume. Therefore, their mRNA and protein concentrations change as the cell volume increases, which often have crucial biological functions such as cell-cycle regulation. However, the biophysical mechanism underlying the nonlinear scaling between gene expression and cell volume is still unclear. In this work, we show that the nonlinear scaling is a direct consequence of the heterogeneous recruitment abilities of promoters to RNA polymerases based on a gene expression model at the whole-cell level. Those genes with weaker (stronger) recruitment abilities than the average ability spontaneously exhibit superlinear (sublinear) scaling with cell volume. Analysis of the promoter sequences and the nonlinear scaling of Saccharomyces cerevisiae’s mRNA levels shows that motifs associated with transcription regulation are indeed enriched in genes exhibiting nonlinear scaling, in concert with our model.

scholarly journals Patient-Derived Head and Neck Cancer Organoids Recapitulate EGFR Expression Levels of Respective Tissues and Are Responsive to EGFR-Targeted Photodynamic Therapy

2019 ◽  
Vol 8 (11) ◽  
pp. 1880 ◽  
Author(s):  
Else Driehuis ◽  
Sacha Spelier ◽  
Irati Beltrán Hernández ◽  
Remco de Bree ◽  
Stefan M. Willems ◽  
...  
Keyword(s):  
Photodynamic Therapy ◽  
Head And Neck ◽  
Three Dimensional ◽  
Growth Factor Receptor ◽  
Therapeutic Interventions ◽  
Expression Levels ◽  
Tumor Patient ◽  
Normal Tissues ◽  
Egfr Expression

Patients diagnosed with head and neck squamous cell carcinoma (HNSCC) are currently treated with surgery and/or radio- and chemotherapy. Despite these therapeutic interventions, 40% of patients relapse, urging the need for more effective therapies. In photodynamic therapy (PDT), a light-activated photosensitizer produces reactive oxygen species that ultimately lead to cell death. Targeted PDT, using a photosensitizer conjugated to tumor-targeting molecules, has been explored as a more selective cancer therapy. Organoids are self-organizing three-dimensional structures that can be grown from both normal and tumor patient-material and have recently shown translational potential. Here, we explore the potential of a recently described HNSCC–organoid model to evaluate Epidermal Growth Factor Receptor (EGFR)-targeted PDT, through either antibody- or nanobody-photosensitizer conjugates. We find that EGFR expression levels differ between organoids derived from different donors, and recapitulate EGFR expression levels of patient material. EGFR expression levels were found to correlate with the response to EGFR-targeted PDT. Importantly, organoids grown from surrounding normal tissues showed lower EGFR expression levels than their tumor counterparts, and were not affected by the treatment. In general, nanobody-targeted PDT was more effective than antibody-targeted PDT. Taken together, patient-derived HNSCC organoids are a useful 3D model for testing in vitro targeted PDT.

scholarly journals Codon usage is an important determinant of gene expression levels largely through its effects on transcription

2016 ◽  
Vol 113 (41) ◽  
pp. E6117-E6125 ◽  
Author(s):  
Zhipeng Zhou ◽  
Yunkun Dang ◽  
Mian Zhou ◽  
Lin Li ◽  
Chien-hung Yu ◽  
...  
Keyword(s):  
Gene Expression ◽  
Codon Usage ◽  
Important Determinant ◽  
Mrna Translation ◽  
Mrna Levels ◽  
Protein Coding ◽  
Expression Levels ◽  
Highly Expressed Genes ◽  
The Impact ◽  
Gene Expression Levels

Codon usage biases are found in all eukaryotic and prokaryotic genomes, and preferred codons are more frequently used in highly expressed genes. The effects of codon usage on gene expression were previously thought to be mainly mediated by its impacts on translation. Here, we show that codon usage strongly correlates with both protein and mRNA levels genome-wide in the filamentous fungus Neurospora. Gene codon optimization also results in strong up-regulation of protein and RNA levels, suggesting that codon usage is an important determinant of gene expression. Surprisingly, we found that the impact of codon usage on gene expression results mainly from effects on transcription and is largely independent of mRNA translation and mRNA stability. Furthermore, we show that histone H3 lysine 9 trimethylation is one of the mechanisms responsible for the codon usage-mediated transcriptional silencing of some genes with nonoptimal codons. Together, these results uncovered an unexpected important role of codon usage in ORF sequences in determining transcription levels and suggest that codon biases are an adaptation of protein coding sequences to both transcription and translation machineries. Therefore, synonymous codons not only specify protein sequences and translation dynamics, but also help determine gene expression levels.

VEGF receptor 1 and heparanase expression as prognostic factors in cholangiocellular carcinoma.

2011 ◽  
Vol 29 (4_suppl) ◽  
pp. 226-226
Author(s):  
E. Goekkurt ◽  
J. Stoehlmacher ◽  
D. E. Aust ◽  
P. V. Danenberg ◽  
K. D. Danenberg ◽  
...  
Keyword(s):  
Gene Expression ◽  
Prognostic Factors ◽  
Egf Receptor ◽  
Cholangiocellular Carcinoma ◽  
Vegf Receptor ◽  
Mrna Levels ◽  
Internal Reference ◽  
Logrank Test ◽  
Expression Levels ◽  
Ffpe Tissues

226 Background: Cholangiocellular carcinoma (CCC) remains to be a tumor with very few treatment choices and limited prognosis. In this study, we sought to determine the prognostic role of VEGF receptor 1 (VEGFR1), heparanase (HPSE) and EGF receptor (EGFR) gene expression in patients with resected CCC. Methods: 47 formallin-fixed paraffin embedded FFPE tumor samples from patients with resected CCC were analyzed. FFPE tissues were dissected using laser-captured microdissection and analyzed for VEGFR1, HPSE and EGFR mRNA expression using a quantitative real-time RT-PCR method. Gene expression values (relative mRNA levels) are expressed as ratios between the target gene and internal reference genes (beta-actin, b2mg, rplp2, sdha). Results: VEGFR1 and HPSE expression levels were significantly associated with overall survival (OS). Patients expressing low levels of VEGFR1 displayed a median OS of 23.2 months compared to 5.3 months in patients with high VEGFR1 expression (p=0.006, logrank test). Patients with low HPSE expression had a median OS of 19.8 months compared to 10.0 months in patients with high HPSE expression (p=0.02, logrank test). EGFR and PDGFRα expression were significantly associated with HPSE and VEGFR1 expression (p=0.03 and p<0.0001, respectively). Conclusions: These results suggest that VEGFR1 and HPSE gene expression levels may play a role as prognostic factors in patients with CCC. Further studies are warranted to study these associations. [Table: see text]

Correlation of messenger RNA expression patterns of ERCC1, TS, EGFR, and VEGFR2 with KRAS and BRAF mutational status in advanced colorectal cancer: Implications for targeted therapies.

2013 ◽  
Vol 31 (4_suppl) ◽  
pp. 383-383
Author(s):  
Martin K. H. Maus ◽  
Craig Stephens ◽  
Stephanie H. Astrow ◽  
Peter Philipp Grimminger ◽  
Dongyun Yang ◽  
...  
Keyword(s):  
Gene Expression ◽  
Colorectal Cancer ◽  
Mrna Expression ◽  
Advanced Colorectal Cancer ◽  
Expression Patterns ◽  
Mrna Levels ◽  
Expression Levels ◽  
Mutational Status ◽  
Mrna Expression Levels ◽  
Gene Expression Levels

383 Background: Gene expression levels of ERCC1, TS, EGFR and VEGFR2 may have predictive value for the personalized use of standard chemotherapeutics as well as agents targeting the EGFR and VEGF pathways and the efficacy of EGFR directed monoclonal antibodies like panitumumab and cetuximab has been confirmed to be dependent on wt KRAS and wt BRAF in patients with advanced colorectal cancer. We investigated the correlations between KRAS/BRAF mutational status and the mRNA expression levels of these genes. Methods: Formalin-fixed paraffin-embedded tumor specimens from 600 patients with advanced colorectal adenocarcinoma were microdissected and DNA and RNA was extracted. Specifically designed primers and probes were used to detect 7 different base substitutions in codon 12 and 13 of KRAS, V600E mutations in BRAF and the expression levels of ERCC1, TS, EGFR and VEGFR2 by RT-PCR. Results: Mt KRAS tumors had significantly lower TS and EGFR gene expression levels compared with wt KRAS (p<0,001), whereas mt BRAF tumors showed significantly increased TS and EGFR mRNA levels compared to wt BRAF (p<0,001). Mt BRAF tumors showed significantly higher mRNA levels than mt KRAS tumors (p<0,001). ERCC1 and VEGFR2 mRNA levels were significantly down-regulated in mt KRAS specimen (p<0,001), but showed no significant correlation with BRAF mutational status. Conclusions: KRAS and BRAF mutations are associated with opposite mRNA expression levels for TS and EGFR. Recently, resistance to BRAF inhibition in mt BRAF colorectal tumors has been shown in preclinical models to be associated with up-regulation of EGFR. Our data suggests that BRAF mutants are associated with high EGFR levels at the time of diagnosis, and not necessarily part of an acquired mechanism of resistance. Significantly lower mRNA expression levels of VEGFR2 in mt KRAS tumors may explain lower response to angiogenesis inhibition seen in the TML study.

scholarly journals Epstein-Barr Virus Latent Membrane Protein 1 Modulates Distinctive NF-κB Pathways through C-Terminus-Activating Region 1 To Regulate Epidermal Growth Factor Receptor Expression

2010 ◽  
Vol 84 (13) ◽  
pp. 6605-6614 ◽  
Author(s):  
Che-Pei Kung ◽  
Nancy Raab-Traub
Keyword(s):  
Gene Expression ◽  
Epstein Barr Virus ◽  
Growth Factor Receptor ◽  
Latent Membrane Protein ◽  
Latent Membrane Protein 1 ◽  
Barr Virus ◽  
Egfr Expression ◽  
C Terminus ◽  
Epidermal Growth ◽  
Epstein Barr

ABSTRACT Epstein-Barr Virus (EBV) latent membrane protein 1 (LMP1) is required for EBV B-lymphocyte transformation, transforms rodent fibroblasts, and can induce lymphoma and epithelial hyperplasia in transgenic mice. Two domains have been identified within the intracellular carboxy terminus that can activate NF-κB, C-terminus-activating region 1 (CTAR1) and CTAR2, through interactions with tumor necrosis receptor-associated factors (TRAFs). CTAR1 can activate both the canonical and noncanonical NF-κB pathways and has unique effects on cellular gene expression. The epidermal growth factor receptor (EGFR) is highly induced by LMP1-CTAR1 in epithelial cells through activation of a novel NF-κB form containing p50 homodimers and Bcl-3. To further understand the regulation of NF-κB in CTAR1-induced EGFR expression, we evaluated the ability of CTAR1 to induce EGFR in mouse embryonic fibroblasts (MEFs) defective for different NF-κB effectors. CTAR1-mediated EGFR induction required the N F-κB- i nducing k inase (NIK) but not the IκB kinase (IKK) complex components that regulate canonical or noncanonical NF-κB pathways. CTAR1-mediated induction of nuclear p50 occurred in IKKβ-, IKKγ-, and NIK-defective MEFs, indicating that this induction is not dependent on the canonical or noncanonical NF-κB pathways. EGFR and nuclear p50 were expressed at high levels in TRAF2−/− fibroblasts and were not induced by CTAR1. In TRAF3−/− MEFs, CTAR1 induced nuclear p50 but did not affect basal levels of STAT3 serine phosphorylation or induce EGFR expression. EGFR was induced by LMP1 in TRAF6−/− MEFs. These findings suggest that this novel NF-κB pathway is differentially regulated by TRAF2 and TRAF3, and that distinct interactions of LMP1 and its effectors regulate LMP1-mediated gene expression.

Prepubertal male rats with high rates of germ-cell apoptosis present exacerbated rates of germ-cell apoptosis after serotonin depletion

2016 ◽  
Vol 28 (6) ◽  
pp. 806 ◽  
Author(s):  
Néstor Méndez Palacios ◽  
María Elena Ayala Escobar ◽  
Maximino Méndez Mendoza ◽  
Rubén Huerta Crispín ◽  
Octavio Guerrero Andrade ◽  
...  
Keyword(s):  
Gene Expression ◽  
Germ Cell ◽  
Mrna Expression ◽  
Cell Apoptosis ◽  
Differential Sensitivity ◽  
Male Rats ◽  
Mrna Levels ◽  
Germ Cell Apoptosis ◽  
Expression Of Genes ◽  
Prepubertal Rats

Male germ-cell apoptosis occurs naturally and can be increased by exposure to drugs and toxic chemicals. Individuals may have different rates of apoptosis and are likely to also exhibit differential sensitivity to outside influences. Previously, we reported that p-chloroamphetamine (pCA), a substance that inhibits serotonin synthesis, induced germ-cell apoptosis in prepubertal male rats. Here, we identified prepubertal rats with naturally high or low rates of germ-cell apoptosis and evaluated gene expression in both groups. Bax and Shbg mRNA levels were higher in rats with high rates of germ-cell apoptosis. Rats were then treated with pCA and the neuro-hormonal response and gene expression were evaluated. Treatment with pCA induced a reduction in serotonin concentrations but levels of sex hormones and gonadotrophins were not changed. Rats with initially high rates of germ-cell apoptosis had even higher rates of germ-cell apoptosis after treatment with pCA. In rats with high rates of germ-cell apoptosis Bax mRNA expression remained high after treatment with pCA. On the basis of category, an inverse relationship between mRNA expression of Bax and Bcl2, Bax and AR and Bax and Hsd3b2 was found. Here we provide evidence that innate levels of germ-cell apoptosis could be explained by the level of mRNA expression of genes involved with apoptosis and spermatogenesis.

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