Immune- and tumor-intrinsic gene expression profiles of response or resistance to tislelizumab as monotherapy or in combination with chemotherapy in non-small cell lung cancer (NSCLC).

2020 ◽  
Vol 38 (15_suppl) ◽  
pp. e15258-e15258
Author(s):  
Jayesh Desai ◽  
Jie Wang ◽  
Qing Zhou ◽  
Jun Zhao ◽  
Sanjeev Deva ◽  
...  
Keyword(s):  
Gene Expression ◽  
Dna Repair ◽  
Clinical Benefit ◽  
Expression Profiles ◽  
Gene Expression Profiles ◽  
Rank Test ◽  
M2 Macrophage ◽  
Intrinsic Factors ◽  
Expression Of Genes ◽  
Intrinsic Gene

e15258 Background: Tislelizumab, an anti-PD-1 monoclonal antibody, showed clinical benefit for patients (pts) with NSCLC alone (NCT02407990, CTR20160872) and in combination with chemotherapy (NCT03432598). Gene expression profiles (GEP) associated with response and resistance to tislelizumab in these studies were assessed. Methods: The GEP of baseline tumor samples from 59 nonsquamous (NSQ) and 42 squamous (SQ) NSCLC pts treated with tislelizumab monotherapy (mono) as ≥1L treatment, and 16 NSQ and 21 SQ pts treated with tislelizumab plus chemotherapy (combo) as 1L treatment were assessed using the 1392-gene HTG GEP EdgeSeq panel. NSQ and SQ cohorts were analyzed separately due to distinct GEP features shown by PCA and t-SNE clustering. Results: Tislelizumab mono and combo showed antitumor activity in NSCLC (Table). In 80 biomarker-evaluable samples, inflamed tumor signatures (inflammatory GEP; antigen presentation GEP) were associated with longer overall survival (log-rank test, NSQ mono: P=0.04, 0.003; NSQ combo: P=0.05, 0.02; SQ combo: P=0.06, 0.06). Monotherapy non-responders (NRs) were clustered into 2 subgroups (NR1, NR2) with distinct GEPs. Compared with responders, NR1 had proliferation signatures (elevated cell cycle [CC] and DNA repair) in both NSQ ( P=0.2, 0.02) and SQ ( P=0.03, 0.4) cohorts, trending toward low inflamed tumor signatures. In NR pts receiving combo, CC and DNA repair signatures were not enriched, and high CC and DNA repair scores were observed in some SQ combo responders versus NRs ( P=0.2, 0.02). NR2 had higher M2 macrophage and Treg cell signatures versus responders in both NSQ and SQ mono, despite high inflamed tumor and low proliferation signatures. NR2 also had increased expression of genes related to immune regulation and angiogenesis, including PIK3CD, CCR2, CD244, IRAK3, and MAP4K1 ( P<0.05) in NSQ, and PIK3CD, CCR2, CD40, CD163, MMP12, VEGFC, and TEK ( P<0.05) in SQ. Conclusions: Clinical benefit in pts with NSCLC receiving tislelizumab (mono or combo) was associated with high inflamed tumor signatures, while elevated immune suppressive cell signatures may indicate resistance. High proliferation signatures were associated with resistance to monotherapy, but not to combination therapy. Both immune- and tumor-intrinsic factors may be considered for validation in future clinical trials. [Table: see text]

Abstract 808: Intrinsic gene expression profiles of gliomas are a better predictor of survival than histology

2010 ◽  
Author(s):  
Lonneke Gravendeel ◽  
Mathilde Kouwenhoven ◽  
Olivier Gevaert ◽  
Johan de Rooi ◽  
Andrew Stubbs ◽  
...  
Keyword(s):  
Gene Expression ◽  
Expression Profiles ◽  
Gene Expression Profiles ◽  
Intrinsic Gene

Monitoring expression of genes involved in drug metabolism and toxicology using DNA microarrays

2001 ◽  
Vol 5 (4) ◽  
pp. 161-170 ◽  
Author(s):  
DAVID GERHOLD ◽  
MEIQING LU ◽  
JIAN XU ◽  
CHRISTOPHER AUSTIN ◽  
C. THOMAS CASKEY ◽  
...  
Keyword(s):  
Gene Expression ◽  
Drug Metabolism ◽  
Stress Responses ◽  
Dna Microarrays ◽  
Expression Profiles ◽  
Gene Expression Profiles ◽  
Metabolic Effects ◽  
Microarray Technology ◽  
Drug Candidates ◽  
Expression Of Genes

Oligonucleotide DNA microarrays were investigated for utility in measuring global expression profiles of drug metabolism genes. This study was performed to investigate the feasibility of using microarray technology to minimize the long, expensive process of testing drug candidates for safety in animals. In an evaluation of hybridization specificity, microarray technology from Affymetrix distinguished genes up to a threshold of ∼90% DNA identity. Oligonucleotides representing human cytochrome P-450 gene CYP3A5 showed heterologous hybridization to CYP3A4 and CYP3A7 RNAs. These genes could be clearly distinguished by selecting a subset of oligonucleotides that hybridized selectively to CYP3A5. Further validation of the technology was performed by measuring gene expression profiles in livers of rats treated with vehicle, 3-methylcholanthrene (3MC), phenobarbital, dexamethasone, or clofibrate and by confirming data for six genes using quantitative RT-PCR. Responses of drug metabolism genes, including CYPs, epoxide hydrolases ( EHs), UDP-glucuronosyl transferases ( UGTs), glutathione sulfotransferases ( GSTs), sulfotransferases ( STs), drug transporter genes, and peroxisomal genes, to these well-studied compounds agreed well with, and extended, published observations. Additional gene regulatory responses were noted that characterize metabolic effects or stress responses to these compounds. Thus microarray technology can provide a facile overview of gene expression responses relevant to drug metabolism and toxicology.

scholarly journals Dynamic Clustering of Gene Expression

2012 ◽  
Vol 2012 ◽  
pp. 1-12 ◽  
Author(s):  
Lingling An ◽  
R. W. Doerge
Keyword(s):  
Gene Expression ◽  
Developmental Stages ◽  
Expression Profiles ◽  
Gene Expression Profiles ◽  
Optimal Number ◽  
Sequential Data ◽  
Dynamic Clustering ◽  
Biological Processes ◽  
Time Frequency ◽  
Expression Of Genes

It is well accepted that genes are simultaneously involved in multiple biological processes and that genes are coordinated over the duration of such events. Unfortunately, clustering methodologies that group genes for the purpose of novel gene discovery fail to acknowledge the dynamic nature of biological processes and provide static clusters, even when the expression of genes is assessed across time or developmental stages. By taking advantage of techniques and theories from time frequency analysis, periodic gene expression profiles are dynamically clustered based on the assumption that different spectral frequencies characterize different biological processes. A two-step cluster validation approach is proposed to statistically estimate both the optimal number of clusters and to distinguish significant clusters from noise. The resulting clusters reveal coordinated coexpressed genes. This novel dynamic clustering approach has broad applicability to a vast range of sequential data scenarios where the order of the series is of interest.

scholarly journals Characteristic Features of the Transcriptome in a Rat Strain with Audiogenic Epilepsy

2022 ◽  
Author(s):  
Lyubov N. Chuvakova ◽  
Sergey Yu. Funikov ◽  
Artem I. Davletshin ◽  
Irina B. Fedotova ◽  
Mikhail B. Evgen'ev ◽  
...  
Keyword(s):  
Gene Expression ◽  
Dna Repair ◽  
Molecular Mechanisms ◽  
Expression Profiles ◽  
Gene Expression Profiles ◽  
Mapk Signaling ◽  
Repair System ◽  
Audiogenic Epilepsy ◽  
Rat Strain ◽  
Characteristic Features

Audiogenic epilepsy (AE), developing in rodent strains in response to sound, is widely used as the model of generalized convulsive epilepsy, while the molecular mechanisms determining AE are currently poorly understood. The brain region that is crucial for AE development isthe inferior and superior colliculi (IC, SC). We compared IC-SC gene expression profiles in rats with different AE susceptibility using transcriptome analysis.The transcriptomes were obtained from the IC-SC of Wistar rats (with no AE), Krushinsky-Molodkina (KM) strain rats (100% AE susceptible), and ”0” strain rats (with no AE) selected from F2 KM x Wistar hybrids for AE absence. KM gene expression displayed characteristic differences inboth of the strains that were not susceptible to AE. There was increased expression of a number of genes responsible for positive regulation of the MAPK signaling cascade, as well as of genes responsible for the production of interferon and several other cytokines. An increase in the expression levels of theTTR gene was found in KM rats, as well as significantly lower expression of the Msh3 gene (involved in post-replicative DNA repair systems). AE was also describedin the 101/HY mouse strain with a mutation in the locus controlling DNA repair. The DNA repair system defects could be the primary factor leading to the accumulation of mutations, which, in turn, promote AE. Keywords: udiogenic seizure, KM strain, transcriptome, TTR gene, Msh3 gene, DNA repair

scholarly journals The tongue biofilm metatranscriptome identifies metabolic pathways associated with halitosis and its prevention

2021 ◽  
Author(s):  
Miguel Carda-Dieguez ◽  
Bob T. Rosier ◽  
Sandra Lloret ◽  
Carmen Llena ◽  
Alex Mira
Keyword(s):  
Gene Expression ◽  
Hydrogen Sulfide ◽  
Expression Profiles ◽  
Gene Expression Profiles ◽  
Fusobacterium Nucleatum ◽  
Sulfide Concentration ◽  
Methyl Mercaptan ◽  
Over Expression ◽  
Expression Of Genes ◽  
Taxonomic Studies

Halitosis is an oral condition caused by an increase in the concentration of volatile sulfur compounds (VSCs), such as methyl mercaptan and hydrogen sulfide, generated as a consequence of bacterial metabolism on the tongue biofilm. Microbial communities on the tongue of halitosis patients have been studied by bacterial culture, 16S rRNA taxonomic studies and metagenomics. However, there are currently no reports on the microbial gene-expression profiles. In this study, we performed RNAseq of tongue coating samples from control individuals and halitosis patients with different levels and composition of VSCs, as determined by gas chromatography. In this metatranscriptomic study, the activity of Streptococcus, Veillonella and Rothia species was associated with halitosis-free individuals while Prevotella, Fusobacterium and Leptotrichia species were associated with halitosis. Although methyl mercaptan is considered an indicator of halitosis, the metatranscriptome of patients in which only this VSC was present in elevated levels was similar to that of halitosis-free individuals. Veillonella dispar, Streptococcus parasanguinis and Rothia mucilaginosa were over-represented in halitosis-free communities in comparison to the rest of the groups, suggesting that these species could be used as a halitosis-free biomarkers. In contrast, the abundance of Prevotella shahi and Fusobacterium nucleatum were significantly higher when hydrogen sulfide concentration was over the established halitosis-threshold, making these species putative halitosis biomarkers. Finally, gene expression profiles showed a significant over-expression of genes involved in L-cysteine and L-homocysteine synthesis in halitosis-free individuals and an over-expression of genes responsible for cysteine degradation into hydrogen sulfide in halitosis patients. In addition, nitrate reduction into nitrite was also over-expressed in halitosis-free patients. In conclusion, halitosis was associated with communities that degrade amino acids and reduce sulfide, whereas tongue communities that produce L-cysteine from hydrogen sulfide and that reduce nitrate were associated with the absence of halitosis. The latter could provide new strategies to treat this condition.

The changes of gene expression profiles in hydatidiform mole and choriocarcinoma with hyperplasia of trophoblasts

2004 ◽  
Vol 14 (5) ◽  
pp. 984-997 ◽  
Author(s):  
J. Q. Cui ◽  
Y. F. Shi ◽  
H. J. Zhou ◽  
J. Q. Li
Keyword(s):  
Gene Expression ◽  
Cell Proliferation ◽  
Cdna Microarray ◽  
Expression Profiles ◽  
Hydatidiform Mole ◽  
Gene Expression Profiles ◽  
Small Subunit ◽  
Altered Expression ◽  
Expression Of Genes ◽  
Hydatidiform Moles

The purpose of this study is to investigate changes of gene expression profiles in hydatidiform moles (HM) and choriocarcinoma and to explore causes of trophoblastic hyperplasia. Using cDNA microarray, 4096 genes were analyzed in two pairs of the tissues of HM versus normal villi and in two pairs of normal primary culture trophoblasts versus JAR cell line of choriocarcinoma. The expressions of two genes in normal villi and HM, as well as in JAR and JEG-3, were examined with the help of immunohistochemistry, immunoblot, and reverse transcriptase-polymerase chain reaction in order to confirm the findings of cDNA microarray. Twenty-four genes were upregulated and 65 genes were downregulated in all HM. Four hundred thirty-three genes were upregulated and 380 genes were downregulated in JAR. Forty-six genes were upregulated in both HM and choriocarcinoma, whereas 13 genes were downregulated. Genes associated with the inhibition of cell proliferation were significantly downregulated, whereas genes associated with cell proliferation, malignant transformation, metastasis, and drug resistance were upregulated. Thymidine kinase-1 (TK-1) and small subunit ribonucleotide reductase (RRM-2) were overexpressed in HM, JAR, and JEG-3. The expressions of TK-1 and RRM-2 in moles were positively correlated with proliferative index of trophoblasts. Our results suggest that altered expression of genes exist in HM and choriocarcinoma. Trophoblastic hyperplasia may be involved in the overexpression of DNA synthetic enzymes.

Comparing Initial Wound Healing and Osteogenesis of Porous Tantalum Trabecular Metal and Titanium Alloy Materials

2019 ◽  
Vol 45 (3) ◽  
pp. 173-180 ◽  
Author(s):  
Sompop Bencharit ◽  
Thiago Morelli ◽  
Silvana Barros ◽  
Jackson T. Seagroves ◽  
Steven Kim ◽  
...  
Keyword(s):  
Gene Expression ◽  
Wound Healing ◽  
Titanium Alloy ◽  
Dental Implants ◽  
Expression Profiles ◽  
Gene Expression Profiles ◽  
Trabecular Metal ◽  
Porous Tantalum ◽  
Expression Of Genes ◽  
Conventional Titanium Alloy

Porous tantalum trabecular metal (PTTM) has long been used in orthopedics to enhance neovascularization, wound healing, and osteogenesis; recently, it has been incorporated into titanium alloy dental implants. However, little is known about the biological responses to PTTM in the human oral cavity. We have hypothesized that, compared with conventional titanium alloy, PTTM has a greater expression of genes specific to neovascularization, wound healing, and osteogenesis during the initial healing period. Twelve subjects requiring at least 4 implants in the mandible were enrolled. Four 3 × 5mm devices, including 2 titanium alloy tapered screws and 2 PTTM cylinders, were placed in the edentulous mandibular areas using a split-mouth design. One device in each group was trephined for analysis at 2 and 4 weeks after placement. RNA microarray analysis and ingenuity pathway analysis were used to analyze osteogenesis gene expression and relevant signaling pathways. Compared to titanium alloy, PTTM samples exhibited significantly higher expressions of genes specific to cell neovascularization, wound healing, and osteogenesis. Several genes—including bone morphogenic proteins, collagens, and growth factors—were upregulated in the PTTM group compared to the titanium alloy control. PTTM materials may enhance the initial healing of dental implants by modifying gene expression profiles.

Unique Gene Expression Profiles of AML Patients with CEBPA Mutations.

Blood ◽  
2005 ◽  
Vol 106 (11) ◽  
pp. 745-745
Author(s):  
Bas J. Wouters ◽  
Claudia A. Erpelinck ◽  
Peter J. Valk ◽  
Roel G. Verhaak ◽  
Bob Löwenberg ◽  
...  
Keyword(s):  
Gene Expression ◽  
Expression Profiles ◽  
Gene Expression Profiles ◽  
Dominant Negative ◽  
Differentially Expressed ◽  
Rank Test ◽  
Insertion Mutation ◽  
Wild Type ◽  
Unique Gene ◽  
Cebpa Mutations

Abstract The transcription factor CCAAT/enhancer binding protein alpha (C/EBPalpha) is critical for granulopoiesis. 5–10% of patients with acute myeloid leukemia (AML) carry mutations in the coding region of the CEBPA gene. In a gene expression profiling study of 285 de novo AML patients we previously identified sixteen distinct clusters of AML (Valk et al, N Engl J Med 2004). Eighteen patients (6.3%) carried mutations in CEBPA, and 17 of them were found in two clusters (clusters #4 and #15), indicating that patients with CEBPA mutations exhibit unique gene expression profiles. In cluster #15, all specimens (n=8) carried CEBPA mutations, whereas in cluster #4 CEBPA mutations were found in 9 out of 15 cases. The other 6 cases in this subgroup showed low or no CEBPA mRNA expression, and in 4 of the latter the gene appeared to be switched off by CpG-hypermethylation. We sought to understand why CEBPA mutations were found in two separate clusters, and asked whether we could identify differences between the two clusters. We found no difference when analyzing CEBPA mutation types as most specimens in both clusters carried both an N-terminal truncation and a C-terminal in-frame insertion mutation. Morphologically, specimens in cluster #4 appeared to be less differentiated as compared to patients in cluster #15 (predominant FAB-types being M1 and M2, respectively). With respect to overall survival, patients in cluster #15 tend to have a slightly worse prognosis than patients with mutations in cluster #4 (Kaplan-Meier method, log-rank test, p=0.03). Although two separate clusters were formed, we felt that genes present in expression profiles of both cluster #4 and #15 could be potentially interesting as they could be linked to defective C/EBPalpha functioning. Strikingly, out of the 22 genes differentially expressed in cluster #15, 12 were also differentially expressed in cluster #4, including CTNNA1, TUBB-5, NDFIP1, SFXN3, KIAA0746 and TENS1. Interestingly, all 12 genes were significantly downregulated, suggesting that they could be targets of wild type C/EBPalpha and/or downregulated by mutated C/EBPalpha. To test this hypothesis, we introduced either wild type or mutant CEBPA-ER into 32Dcl1, a cell line model constitutively expressing the human G-CSFR. In line with previous reports, we found that activation of C/EBPalpha by addition of beta-estradiol resulted in proliferation arrest and differentiation of these cells within two days, even in the presence of IL-3. Expression levels of the C/EBPalpha target gene CSF3R increased drastically (12-fold after 24 hours, 53-fold after 48 hours) upon stimulation with beta-estradiol as compared to unstimulated or empty vector control clones. Experiments with clones expressing a C-terminal mutant carrying an 18-nt insertion in the bZIP region showed that proliferation was only modestly inhibited and that differentiation was severely impaired both in the presence of IL-3 or G-CSF. Interestingly, no upregulation of the CSF3R gene was observed following beta-estradiol stimulation of mutant CEBPA-ER in the presence of IL-3. Moreover, activation of mutant C/EBPalpha counteracted the induction of CSF3R expression observed following G-CSF activation. These findings suggest that C-terminal C/EBPalpha mutants can have a dominant negative role in AML. Our studies demonstrate that 32Dcl1-CEBPA-ER cells provide a useful model to further elucidate the possible relationships of C/EBPalpha and C/EBPalpha mutants with differentially expressed genes identified in the gene expression studies.

scholarly journals BAX Redistribution Induces Apoptosis Resistance and Selective Stress Sensitivity in Human HCC

Cancers ◽  
2020 ◽  
Vol 12 (6) ◽  
pp. 1437
Author(s):  
Kathrin Funk ◽  
Carolin Czauderna ◽  
Ramona Klesse ◽  
Diana Becker ◽  
Jovana Hajduk ◽  
...  
Keyword(s):  
Gene Expression ◽  
Dna Repair ◽  
Expression Profiles ◽  
Tumor Biology ◽  
Gene Expression Profiles ◽  
Parp Inhibition ◽  
Molecular Characteristics ◽  
Apoptosis Resistance ◽  
Molecular Features ◽  
The Status

Cancer therapies induce differential cell responses, ranging from efficient cell death to complete stress resistance. The BCL-2 proteins BAX and BAK govern the cellular decision between survival and mitochondrial apoptosis. Therefore, the status of BAX/BAK regulation can predict the cellular apoptosis predisposition. Relative BAX/BAK localization was analyzed in tumor and corresponding non-tumor samples from 34 hepatocellular carcinoma (HCC) patients. Key transcriptome changes and gene expression profiles related to the status of BAX regulation were applied to two independent cohorts including over 500 HCC patients. The prediction of apoptotic response was tested using cell lines and polyclonal tumor isolates. Cellular protection from BAX was confirmed by challenging cells with mitochondrial BAX. We discovered a subgroup of HCC with selective protection from BAX-dependent apoptosis. BAX-protected tumors showed enrichment of signaling pathways associated with oxidative stress response and DNA repair as well as increased genetic heterogeneity. Gene expression profiles characteristic to BAX-specific protection are enriched in poorly differentiated HCCs and show significant association to the overall survival of HCC patients. Consistently, addiction to DNA repair of BAX-protected cancer cells caused selective sensitivity to PARP inhibition. Molecular characteristics of BAX-protected HCC were enriched in cells challenged with mitochondrial BAX. Our results demonstrate that predisposition to BAX activation impairs tumor biology in HCC. Selective BAX inhibition or lack thereof delineates distinct subgroups of HCC patients with molecular features and differential response pattern to apoptotic stimuli and inhibition of DNA repair mechanisms.

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