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Nayak, Ketul, Hiral Panchal, Shivani Patel, and Devam Desai. "SIRNA GENE THERAPY: A REVIEW." International Journal of Advanced Research 8, no. 10 (October 31, 2020): 1121–26. http://dx.doi.org/10.21474/ijar01/11942.
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RNA inference is new concept in gene therapy it acts by expression of specific genes to treat various diseases like cancer. It is also called as RNAi. In presence of dicer enzyme long double stranded RNA (dsRNA) is cut to small interfering RNAs called SiRNAs. SiRNAs are part of RNAi. It is mainly pursued for cancer therapy. It is the new promising agent which can produce specific gene expression and also post transcriptional gene regulation process for disease treatment. In this current review I gathered lots of basic information about SiRNA like its structure, design, delivery system etc in short sweet manner.
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Zhang, Junlong. "Special delivery: Small RNAs silencing gene expression." Biochemist 26, no. 5 (October 1, 2004): 20–23. http://dx.doi.org/10.1042/bio02605020.
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RNA interference (RNAi), which refers to RNA-induced transcriptional gene silencing, is a natural phenomenon that exists widely in living organisms. Recent advances in RNAi research indicate that RNAi technology is a powerful tool in studying gene function and has a great potential in gene therapy. Although many methods, including viral and non-viral vectors, have been used to deliver small interference RNA molecules into cells and animals, development of better delivery methods is still crucial for the application of RNAi technology in both basic research and gene therapy.
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Huang, Wei-Hsuan, Chao-Neng Tseng, Jen-Yang Tang, Cheng-Hong Yang, Shih-Shin Liang, and Hsueh-Wei Chang. "RNA Editing and Drug Discovery for Cancer Therapy." Scientific World Journal 2013 (2013): 1–5. http://dx.doi.org/10.1155/2013/804505.
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RNA editing is vital to provide the RNA and protein complexity to regulate the gene expression. Correct RNA editing maintains the cell function and organism development. Imbalance of the RNA editing machinery may lead to diseases and cancers. Recently, RNA editing has been recognized as a target for drug discovery although few studies targeting RNA editing for disease and cancer therapy were reported in the field of natural products. Therefore, RNA editing may be a potential target for therapeutic natural products. In this review, we provide a literature overview of the biological functions of RNA editing on gene expression, diseases, cancers, and drugs. The bioinformatics resources of RNA editing were also summarized.
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Caplen, N. J. "Gene Therapy Progress and Prospects. Downregulating gene expression: the impact of RNA interference." Gene Therapy 11, no. 16 (August 2004): 1241–48. http://dx.doi.org/10.1038/sj.gt.3302324.
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Lei, Sibei, Xueyan Zhang, Jingmei Li, Yan Gao, Jieping Wu, Xingmei Duan, and Ke Men. "Current Progress in Messenger RNA-Based Gene Therapy." Journal of Biomedical Nanotechnology 16, no. 7 (July 1, 2020): 1018–44. http://dx.doi.org/10.1166/jbn.2020.2961.
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Based on its rapid expression, simple sequence composition, low immunogenicity, and flexible modification possibilities, in vitro synthesized mRNA has demonstrated strong potential as a candidate for gene therapy. Many efforts have been made to enhance its therapeutic efficacy and safety. Profiting from the development in pathogenesis and materials science, much progress has been achieved in mRNA-based therapy studies. Many mRNA-derived therapeutics including vaccines, antibodies, cytokines, and growth factors have emerged for the treatment of diverse diseases that have multiple modes of action. Novel delivery vectors with enhanced capacity, safety, and properties have been developed to meet the demands of mRNA delivery. Advanced strategies like library screening, environment interaction, and bio-inspiration materials have been used in the investigation process and produced valuable results. In this review, we summarize and discuss recent advances in mRNA-based gene therapy studies.
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Blum and Moradpour. "Recombinant drugs and gene therapy." Therapeutische Umschau 56, no. 12 (December 1, 1999): 730–37. http://dx.doi.org/10.1024/0040-5930.56.12.730.
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Ausgehend von der Biologie somatischer Zellen mit Transkription der chromosomalen DNA in messenger RNA (mRNA) und deren Translation in Proteine werden die Prinzipien der Gentechnologie illustriert. Die Gentechnologie ermöglicht die Klonierung, Identifizierung und Charakterisierung von Genen sowie deren Expression mit Synthese von medizinisch relevanten Proteinen. Die Produkte der Gentechnologie sind somit zum einen klonierte Gene, die für die molekulare Diagnostik und die Gentherapie medizinisch bedeutsam sind. Zum anderen sind es in vitro oder in vivo hergestellte Proteine, die als Diagnostika, Therapeutika und Impfstoffe zunehmend Eingang in die klinische Praxis finden.
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Beltran, Himisha, Alexander Wyatt, Edmund Chedgy, Ladan Fazli, Andrea Sboner, Susan Halabi, and Martin Gleave. "Impact of therapy on gene expression in high-risk prostate cancer (PCA) treated with neoadjuvant docetaxel and androgen deprivation therapy." Journal of Clinical Oncology 34, no. 2_suppl (January 10, 2016): 8. http://dx.doi.org/10.1200/jco.2016.34.2_suppl.8.
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8 Background: Molecular analyses of neoadjuvant post-treatment radical prostatectomy (RP) specimens has been challenging as often times only microscopic foci remain present at time of RP precluding RNA-seq. DNA analysis alone in the absence of expression may be suboptimal in elucidating complex mechanisms of resistance and/or prognostic risk stratification. We therefore set out to develop an assay that could quantify mRNA expression in treated and untreated PCA using formalin fixed paraffin embedded (FFPE) tissues. Methods: We evaluated 40 untreated and post-treatment FFPE specimens as well as patient-matched pre-treated needle biopsies and baseline clinical data from patients enrolled on CALGB 90203: a randomized phase 3 trial comparing noeadjuvant docetaxel and ADT followed by RP vs RP alone for men with high risk localized PCA. High-density tumor areas were selected for RNA extraction (min 50ng RNA). We used NanoString nCounter to quantify gene expression of a custom panel of 75 genes including AR and androgen regulated, neural/neuroendocrine (NE), EMT, cell cycle, hormone receptors, TMPRSS-ERG, ARv7 splice variant, and housekeeper genes. mRNA data was integrated with matched whole exome sequencing data. Frozen specimens and RNA-Seq (n = 7) were used for QC and comparative analysis. Results: Quantitative expression using Nanostring showed high correlation with RNA-seq of patient-matched frozen tissue (Spearman coefficient 0.9). There was significant upregulation of AR and the ARv7 expression following treatment, as well as a subset of NE and EMT genes; three high chromogranin A outlier cases were identified in the treatment arm. There was an overall higher AR score in treated cases (based on expression of 30 AR signaling genes) compared to untreated, along the spectrum of CRPC. Conclusions: These data support the feasibility of quantifying gene expression in neoadjuvant-treated PCA cases with limited FFPE tissue requirement. Extensive characterization of AR status and NE/EMT genes identifies molecular outliers that can arise post-treatment and provides new insight into the heterogeneity of treatment response and potential early markers of resistance. Clinical trial information: NCT00430183.
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DelaFlor-Weiss, E., C. Richardson, M. Ward, A. Himelstein, L. Smith, S. Podda, M. Gottesman, I. Pastan, and A. Bank. "Transfer and expression of the human multidrug resistance gene in mouse erythroleukemia cells." Blood 80, no. 12 (December 15, 1992): 3106–11. http://dx.doi.org/10.1182/blood.v80.12.3106.3106.
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Abstract Gene therapy in humans requires the transplantation of genetically modified cells, and it is important to select only those cells capable of expressing high levels of protein from the transferred gene. Expression of the human multiple drug resistance (MDR) gene confers resistance to a variety of compounds in vitro and in vivo. To determine the feasibility of conferring recipient erythroid cells with the MDR phenotype, we have transduced mouse erythroleukemia cells (MELC) with the MDR gene in a retroviral vector. We show here that MELC clones resistant to exposure to colchicine (an MDR-responsive agent) can be isolated, and demonstrate high levels of MDR RNA and protein expression. Increasing doses of colchicine increase the level of MDR RNA and protein expression significantly. These results indicate that it is possible to transfer and express the human MDR phenotype in mouse erythroid cells by retrovirally mediated gene transfer, and that drug selection can be used to enrich or purify populations of cells containing and expressing this gene.
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DelaFlor-Weiss, E., C. Richardson, M. Ward, A. Himelstein, L. Smith, S. Podda, M. Gottesman, I. Pastan, and A. Bank. "Transfer and expression of the human multidrug resistance gene in mouse erythroleukemia cells." Blood 80, no. 12 (December 15, 1992): 3106–11. http://dx.doi.org/10.1182/blood.v80.12.3106.bloodjournal80123106.
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Gene therapy in humans requires the transplantation of genetically modified cells, and it is important to select only those cells capable of expressing high levels of protein from the transferred gene. Expression of the human multiple drug resistance (MDR) gene confers resistance to a variety of compounds in vitro and in vivo. To determine the feasibility of conferring recipient erythroid cells with the MDR phenotype, we have transduced mouse erythroleukemia cells (MELC) with the MDR gene in a retroviral vector. We show here that MELC clones resistant to exposure to colchicine (an MDR-responsive agent) can be isolated, and demonstrate high levels of MDR RNA and protein expression. Increasing doses of colchicine increase the level of MDR RNA and protein expression significantly. These results indicate that it is possible to transfer and express the human MDR phenotype in mouse erythroid cells by retrovirally mediated gene transfer, and that drug selection can be used to enrich or purify populations of cells containing and expressing this gene.
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Nabilsi, Nancy H., Russell R. Broaddus, Adrienne S. McCampbell, Karen H. Lu, Henry T. Lynch, Lee-may Chen, and David S. Loose. "Sex hormone regulation of survivin gene expression." Journal of Endocrinology 207, no. 2 (August 26, 2010): 237–43. http://dx.doi.org/10.1677/joe-10-0128.
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Survivin (BIRC5) is a cell survival gene that is overexpressed in endometrial cancer and has been implicated to have a physiological role in normal endometrial function. To determine whether survivin gene expression is regulated by reproductive steroid hormones in the human endometrium, RNA was prepared from normal cycling women in the proliferative and secretory phases of the menstrual cycle. RNA was also isolated from 21 endometrial biopsies from premenopausal women at baseline and following 3 months of treatment with depot medroxyprogesterone acetate. Finally, RNA was isolated from endometrial biopsies from ten healthy postmenopausal women participating in a clinical trial of estrogen replacement therapy at baseline and following 6 months of treatment with conjugated equine estrogen. Quantitative RT-PCR analysis was used to determine survivin, insulin-like growth factor binding protein 1 (IGFBP1), Ki67, and IGF1 gene expression levels. Survivin gene expression was highest in the proliferative phase of the menstrual cycle and showed a statistically significant 4-fold increase in expression following chronic treatment with estrogens; this was strongly correlated with increased Ki67, a marker of proliferation. Survivin gene expression decreased 4.6-fold following chronic progestin treatment in the human endometrium. These data suggest that survivin transcript is regulated by estrogens and progestins in the disease-free human endometrium. The data also suggest that survivin transcript may be used as a biomarker of estrogen and progestin treatment efficacy, but validation studies must be conducted to support this conclusion.
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Lundstrom, Kenneth. "RNA Viruses as Tools in Gene Therapy and Vaccine Development." Genes 10, no. 3 (March 1, 2019): 189. http://dx.doi.org/10.3390/genes10030189.
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RNA viruses have been subjected to substantial engineering efforts to support gene therapy applications and vaccine development. Typically, retroviruses, lentiviruses, alphaviruses, flaviviruses rhabdoviruses, measles viruses, Newcastle disease viruses, and picornaviruses have been employed as expression vectors for treatment of various diseases including different types of cancers, hemophilia, and infectious diseases. Moreover, vaccination with viral vectors has evaluated immunogenicity against infectious agents and protection against challenges with pathogenic organisms. Several preclinical studies in animal models have confirmed both immune responses and protection against lethal challenges. Similarly, administration of RNA viral vectors in animals implanted with tumor xenografts resulted in tumor regression and prolonged survival, and in some cases complete tumor clearance. Based on preclinical results, clinical trials have been conducted to establish the safety of RNA virus delivery. Moreover, stem cell-based lentiviral therapy provided life-long production of factor VIII potentially generating a cure for hemophilia A. Several clinical trials on cancer patients have generated anti-tumor activity, prolonged survival, and even progression-free survival.
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Fry, Lewis E., Caroline F. Peddle, Alun R. Barnard, Michelle E. McClements, and Robert E. MacLaren. "RNA Editing as a Therapeutic Approach for Retinal Gene Therapy Requiring Long Coding Sequences." International Journal of Molecular Sciences 21, no. 3 (January 25, 2020): 777. http://dx.doi.org/10.3390/ijms21030777.
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RNA editing aims to treat genetic disease through altering gene expression at the transcript level. Pairing site-directed RNA-targeting mechanisms with engineered deaminase enzymes allows for the programmable correction of G>A and T>C mutations in RNA. This offers a promising therapeutic approach for a range of genetic diseases. For inherited retinal degenerations caused by point mutations in large genes not amenable to single-adeno-associated viral (AAV) gene therapy such as USH2A and ABCA4, correcting RNA offers an alternative to gene replacement. Genome editing of RNA rather than DNA may offer an improved safety profile, due to the transient and potentially reversible nature of edits made to RNA. This review considers the current site-directing RNA editing systems, and the potential to translate these to the clinic for the treatment of inherited retinal degeneration.
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Wu, Yuangang, Xiaoxi Lu, Bin Shen, and Yi Zeng. "The Therapeutic Potential and Role of miRNA, lncRNA, and circRNA in Osteoarthritis." Current Gene Therapy 19, no. 4 (November 18, 2019): 255–63. http://dx.doi.org/10.2174/1566523219666190716092203.
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Background: Osteoarthritis (OA) is a disease characterized by progressive degeneration, joint hyperplasia, narrowing of joint spaces, and extracellular matrix metabolism. Recent studies have shown that the pathogenesis of OA may be related to non-coding RNA, and its pathological mechanism may be an effective way to reduce OA. Objective: The purpose of this review was to investigate the recent progress of miRNA, long noncoding RNA (lncRNA) and circular RNA (circRNA) in gene therapy of OA, discussing the effects of this RNA on gene expression, inflammatory reaction, apoptosis and extracellular matrix in OA. Methods: The following electronic databases were searched, including PubMed, EMBASE, Web of Science, and the Cochrane Library, for published studies involving the miRNA, lncRNA, and circRNA in OA. The outcomes included the gene expression, inflammatory reaction, apoptosis, and extracellular matrix. Results and Discussion: With the development of technology, miRNA, lncRNA, and circRNA have been found in many diseases. More importantly, recent studies have found that RNA interacts with RNA-binding proteins to regulate gene transcription and protein translation, and is involved in various pathological processes of OA, thus becoming a potential therapy for OA. Conclusion: In this paper, we briefly introduced the role of miRNA, lncRNA, and circRNA in the occurrence and development of OA and as a new target for gene therapy.
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Segovia, Jose C., Nestor W. Meza Fellow, Oscar Quintana-Bustamante Fellow, Antonio Puyet, Paula Rio, Juan A. Bueren, and Jose M. Bautista. "Gene Therapy of the Human Erythrocyte Pyruvate Kinase Deficiency." Blood 104, no. 11 (November 16, 2004): 1635. http://dx.doi.org/10.1182/blood.v104.11.1635.1635.
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Abstract Human Erythrocyte Pyruvate Kinase (hRPK) deficiency, an autosomal recessive disorder produced by mutations in the PKLR gene, is known to be the most common cause of chronic non-spherocytic haemolityc anaemia (CNSHA). Patient survival and clinical severity have been associated with the type of mutation found and to a compensatory expression of the broadly tissue distributed M2PK isozyme in their erythrocytes. Mutations in the RPK gene with severe clinical symptoms have been described in our laboratory. The transduction of the wild-type RPK to hematopoietic stem cells from deficient patients may become an alternative therapy in those patients where the mutation cause clinical symptoms. In an attempt to address this hypothesis we constructed retroviral vectors based on the pSF11 backbone and expressing the hRPK and the green fluorescent protein cDNAs in a unique messenger RNA separated by an eukaryotic IRES (SF11RPKXEG). In a first step, murine and human cell lines were transduced with infective supernatants expressing this construct. FACS and western-blot analysis demonstred stable RPK expression in all transduced cell lines. In murine erithroleukemia cell line (MEL) the stability of the expression was screened for more than 20 weeks by EGFP flow cytometry evaluation. The percentage of transduced cells and the intensity of the expression, evaluated by quantification of the mean of fluorescence (MFI) remain unaltered over time. Moreover, the hexamethylene bisacetamide-induced differentiation of MEL cells neither produce any change in RPK or eGFP expression. Secondly, Lin−Sca-1+ murine hematopoietic stem cells were infected in vitro with SF11RPKXEG supernatants and transplanted into myeloablated recipients. Three months post-transplant, very high expression of both RPK and EGFP proteins was detected in mononuclear cells, platelets and, most importantly, mature erythrocytes, the cell target for the treatment of this disease. These findings show that retroviral vectors could be a successful system for RPK delivery and expression in erythroid cells and provide evidences of the gene therapy potential in the phenotypic correction of erythropoietic defects related to human RPK deficiency.
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Trojan, Ladislas A., Piotr Kopinski, Ming X. Wei, Adama Ly, Aleksandra Glogowska, Jolanta Czarny, Alexander Shevelev, Ryszard Przewlocki, Dominique Henin, and Jerzy Trojan. "IGF-I: from diagnostic to triple-helix gene therapy of solid tumors." Acta Biochimica Polonica 49, no. 4 (December 31, 2002): 979–90. http://dx.doi.org/10.18388/abp.2002_3757.
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Alterations in the expression of growth factors and their receptors are associated with the growth and development of human tumors. One such growth factor is IGF-I (insulin-like growth factor I ), a 70-amino-acid polypeptide expressed in many tissues, including brain. IGF-I is also expressed at high levels in some nervous system-derived tumors, especially in glioblastoma. When using IGF-I as a diagnostic marker, 17 different tumors are considered as expressing the IGF-I gene. Malignant glioma, the most common human brain cancer, is usually fatal. Average survival is less than one year. Our strategy of gene therapy for the treatment of gliomas and other solid tumors is based on: 1) diagnostic using IGF-I gene expression as a differential marker, and 2) application of "triple-helix anti-IGF-I" therapy. In the latter approach, tumor cells are transfected with a vector, which encodes an oligoribonucleotide--an RNA strand containing oligopurine sequence which might be capable of forming a triple helix with an oligopurine and/or oligopyrimidine sequence of the promotor of IGF-I gene (RNA-IGF-I DNA triple helix). Human tumor cells transfected in vitro become down-regulated in the production of IGF-I and present immunogenic (MHC-I and B7 expression) and apoptotic characteristics. Similar results were obtained when IGF-I antisense strategy was applied. In both strategies the transfected cells reimplanted in vivo lose tumorigenicity and elicit tumor specific immunity which leads to elimination of established tumors.
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Huang, Huilin, Hengyou Weng, Xiaolan Deng, and Jianjun Chen. "RNA Modifications in Cancer: Functions, Mechanisms, and Therapeutic Implications." Annual Review of Cancer Biology 4, no. 1 (March 9, 2020): 221–40. http://dx.doi.org/10.1146/annurev-cancerbio-030419-033357.
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Over 170 chemical modifications have been identified in protein-coding and noncoding RNAs and shown to exhibit broad impacts on gene expression. Dysregulation of RNA modifications caused by aberrant expression of or mutations in RNA modifiers aberrantly reprograms the epitranscriptome and skews global gene expression, which in turn leads to tumorigenesis and drug resistance. Here we review current knowledge of the functions and underlying mechanisms of aberrant RNA modifications in human cancers, particularly several common RNA modifications, including N6-methyladenosine (m6A), A-to-I editing, pseudouridine (ψ), 5-methylcytosine (m5C), 5-hydroxymethylcytosine (hm5C), N1-methyladenosine (m1A), and N4-acetylcytidine (ac4C), providing insights into therapeutic implications of targeting RNA modifications and the associated machineries for cancer therapy.
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Venturini, Letizia, Matthias Eder, and Michaela Scherr. "RNA-Mediated Gene Silencing in Hematopoietic Cells." Journal of Biomedicine and Biotechnology 2006 (2006): 1–13. http://dx.doi.org/10.1155/jbb/2006/87340.
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In the past few years, the discovery of RNA-mediated gene silencing mechanisms, like RNA interference (RNAi), has revolutionized our understanding of eukaryotic gene expression. These mechanisms are activated by double-stranded RNA (dsRNA) and mediate gene silencing either by inducing the sequence-specific degradation of complementary mRNA or by inhibiting mRNA translation. RNAi now provides a powerful experimental tool to elucidate gene function in vitro and in vivo, thereby opening new exciting perspectives in the fields of molecular analysis and eventually therapy of several diseases such as infections and cancer. In hematology, numerous studies have described the successful application of RNAi to better define the role of oncogenic fusion proteins in leukemogenesis and to explore therapeutic approaches in hematological malignancies. In this review, we highlight recent advances and caveats relating to the application of this powerful new methodology to hematopoiesis.
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Yin, Zhi-Hua, Cai-Ping Ren, Feng Li, Xu-Yu Yang, Hui Li, Ming Zhao, and Kai-Tai Yao. "Suppression of bcl-2 Gene by RNA Interference Increases Chemosensitivity to Cisplatin in Nasopharyngeal Carcinoma Cell Line CNE1." Acta Biochimica et Biophysica Sinica 36, no. 11 (November 1, 2004): 749–53. http://dx.doi.org/10.1093/abbs/36.11.749.
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Abstract To explore the effect of suppressing BCL-2 expression using RNA interference (RNAi) technique in nasopharyngeal carcinoma cell line CNE1. CNE1 cell lines stably expressing shRNAs targeted bcl-2 and GL3 gene were established and gene expression inhibition was assessed by Western blotting analysis. The effect of suppressing bcl-2 by RNAi on cell growth was studied, the apoptosis induction and the sensitization of CNE1 cells to cisplatin were quantified by MTT assay and flow cytometry. The results showed that: stable transfection of CNE1 cells with vectors expressing shRNAs against bcl-2 decreased the expression of BCL-2 protein; suppression of BCL-2 expression did not affect cell proliferation but could increase the chemosensitivity to cisplatin in CNE1 cells. This will help physicians to make some clinical trials of gene therapy on nasopharyngeal carcinoma by RNAi.
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Shaw, Elisabeth J., Brian Haylock, David Husband, Daniel du Plessis, D. Ross Sibson, Peter C. Warnke, and Carol Walker. "Gene Expression in Oligodendroglial Tumors." Analytical Cellular Pathology 33, no. 2 (2010): 81–94. http://dx.doi.org/10.1155/2010/304806.
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Background: Oligodendroglial tumors with 1p/19q loss are more likely to be chemosensitive and have longer survival than those with intact 1p/19q, but not all respond to chemotherapy, warranting investigation of the biological basis of chemosensitivity.Methods: Gene expression profiling was performed using amplified antisense RNA from 28 oligodendroglial tumors treated with chemotherapy (26 serial stereotactic biopsy, 2 resection). Expression of differentially expressed genes was validated by real-time PCR.Results: Unsupervised hierarchical clustering showed clustering of multiple samples from the same case in 14/17 cases and identified subgroups associated with tumor grade and 1p/19q status. 176 genes were differentially expressed, 164 being associated with 1p/19q loss (86% not on 1p or 19q). 94 genes differed between responders and non-responders to chemotherapy; 12 were not associated with 1p/19q loss. Significant differential expression was confirmed in 11/13 selected genes. Novel genes associated with response to therapy includedSSBP2,GFRA1,FAPandRASD1.IQGAP1,INA,TGIF1,NR2F2andMYCBPwere differentially expressed in oligodendroglial tumors with 1p/19q loss.Conclusion: Gene expression profiling using serial stereotactic biopsies indicated greater homogeneity within tumors than between tumors. Genes associated with 1p/19q status or response were identified warranting further elucidation of their role in oligodendroglial tumors.
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Matthew, E., L. Kutcher, and J. Dedman. "Protection of lungs from hyperoxic injury: gene expression analysis of cyclosporin A therapy." Physiological Genomics 14, no. 2 (July 7, 2003): 129–38. http://dx.doi.org/10.1152/physiolgenomics.00130.2002.
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We have previously shown that cyclosporin A (CsA), an inhibitor of protein phosphatase 2B (calcineurin), attenuates hyperoxia-induced reductions in murine lung compliance. CsA protected against hyperoxia-induced changes in neutrophil infiltration, capillary congestion, edema, and hyaline membrane formation. Gene expression studies were conducted to identify the gene expression patterns underlying the protective effects of CsA during hyperoxic lung injury. After 72 h of simultaneous treatment with >95% oxygen and CsA (50 mg·kg−1·day−1), RNA was isolated from murine lungs. RNA from treated and untreated lungs was reverse transcribed to cDNA, competitively hybridized, and used to probe 8,734 complimentary DNAs on the Incyte mouse GEM 1 array. Several known genes and expressed sequence tags (ESTs) showed increased (GenBank accession numbers: AA125385, AA241295, W87197, syntaxin, and cyclin G) or decreased [AA036517, AA267567, AA217009, W82577, uteroglobin, stromal cell-derived factor 1, and surfactant protein C (SP-C)] expression after hyperoxia. Hyperoxia-stimulated reductions in SP-C gene expression were confirmed through Northern blot analysis. The increase in gene expression of one expressed sequence tag (AA125385) with hyperoxia was reversed by CsA treatment. Sequence data demonstrated that this EST has high homology to murine cyclin B1. Western blot analysis did not demonstrate any changes in distal lung cyclin B1 expression after hyperoxia. Protein expression of cyclin B1 in the distal lung was observed in the endothelial cells, bronchiolar epithelial cells, and both the type I and type II alveolar epithelial cells. Further analysis of cyclin B1 may elucidate the protective actions of CsA in hyperoxic injury.
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He, Kevin, S. M. Ali Hosseini Rad, Aarati Poudel, and Alexander Donald McLellan. "Compact Bidirectional Promoters for Dual-Gene Expression in a Sleeping Beauty Transposon." International Journal of Molecular Sciences 21, no. 23 (December 4, 2020): 9256. http://dx.doi.org/10.3390/ijms21239256.
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Promoter choice is an essential consideration for transgene expression in gene therapy. The expression of multiple genes requires ribosomal entry or skip sites, or the use of multiple promoters. Promoter systems comprised of two separate, divergent promoters may significantly increase the size of genetic cassettes intended for use in gene therapy. However, an alternative approach is to use a single, compact, bidirectional promoter. We identified strong and stable bidirectional activity of the RPBSA synthetic promoter comprised of a fragment of the human Rpl13a promoter, together with additional intron/exon structures. The Rpl13a-based promoter drove long-term bidirectional activity of fluorescent proteins. Similar results were obtained for the EF1-α and LMP2/TAP1 promoters. However, in a lentiviral vector, the divergent bidirectional systems failed to produce sufficient titres to translate into an expression system for dual chimeric antigen receptor (CAR) expression. Although bidirectional promoters show excellent applicability to drive short RNA in Sleeping Beauty transposon systems, their possible use in the lentiviral applications requiring longer and more complex RNA, such as dual-CAR cassettes, is limited.
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Renatino Canevarolo, Rafael, Praneeth Reddy Sudalagunta, Maria D. Coelho Siqueira Silva, Mark B. Meads, Priscilla Granados, Anders Berglund, Amit Kulkarni, et al. "A Systems Biology Approach to Identify Mechanisms of Therapy Resistance in Multiple Myeloma." Blood 132, Supplement 1 (November 29, 2018): 3266. http://dx.doi.org/10.1182/blood-2018-99-118784.
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Abstract We describe an approach to identify patient-specific mechanisms of drug resistance in multiple myeloma (MM) patients through a combination of ex vivo chemosensitivity assay using fresh primary samples and gene set enrichment analysis from RNA-Seq and microarray gene expression profiles. Methods: We have performed RNA-Seq on 522 primary MM samples and used a combination of dimensionality reduction analysis (t-SNE) and clustering (fuzzy c-means) to group co-expressing genes in clusters, putatively under control of shared regulatory mechanisms. A data set of microarray gene expression from a second cohort of 762 primary MM samples was used to validate the topology of co-expressing clusters obtained from RNA-Seq. In addition, we have tested drug sensitivity of primary MM samples in an ex vivo reconstruction of the bone marrow tumor microenvironment, including primary human stroma, extra-cellular matrix, and patient-derived soluble factors. 312 of the aforementioned samples were screened against a panel of 95 drugs relevant to MM biology, including PIs -bortezomib (V), carfilzomib (K) and ixazomib (I)-, IMIDs -pomalidomide (P), lenalidomide (R)-, and other standard of care drugs -melphalan (M), dexamethasone (D), doxorubicin (Do), panobinostat (Pa), quisinostat (Q)- and experimental agents -e.g. kinase inhibitors (PKIs), CRM1 inhibitor KPT-330 (Kp) and BCL2 inhibitor ABT-199. Geneset enrichment analysis was performed using GSEA both agnostically, using the clusters of co-expressing genes, and in a knowledge-driven fashion, using pre-established genesets (KEGG, BIOCARTA, HALLMARKS and REACTOME) using LD50 (@96h) or area under the curve (AUC, 0h-96h) as measures of ex vivo drug resistance, and Spearman correlation as ranking metric. Results: We have identified: (a) MM-specific gene expression regulatory architecture, consisting of multiple clusters of co-expressing genes, "gravitating" around a cloud of more loosely correlated genes enriched for super enhancers and the mediator family of genes (Figure 1a); (b) clusters of genes differentially-expressed in ex vivo drug resistant primary samples, confirming that similar mechanisms of resistance were observed for drugs with similar mechanism of action (e.g. Figure 1b); (c) patient and drug-specific mechanisms of resistance (MOR) to therapy, and thus putative means of re-sensitization; and (d) offered candidate synergistic drug combinations based on mutually exclusive mechanisms of resistance. As proof of principle, here we discuss MOR observed in two drugs: ABT-199 and MK2206 (Akt inhibitor). The analysis conducted in MM samples tested with ABT-199 agreed with previous clinical studies in MM, pointing to over-expression of Bcl-xl and Mcl1, as well as under-expression of Bim, Bcl-2, and NOXA in resistant samples. A particular gene cluster, significantly underexpressed in ABT-199-resistant samples, was enriched for ribosomal subunits, regulated by, and contained, MYC, suggesting that MYC and ribogenesis may be linked to Bcl-2 inhibition resistance (Figure 1c). Ex vivo resistance to MK2206 led to ~2/3 of genome under-expression, with the most significant clusters linked to cell cycle (e.g. PLK1, CDK1, CHEK1, etc.) and histone subunits, suggesting a quiescence-mediated mechanism of resistance to Akt inhibition (Figure 1d), in addition to under-expression of AKT, BAD, FOXO and BIM. Importantly, our analysis has observed significant inter-patient heterogeneity, confirming that multiple MOR can be observed within a patient cohort, reinforcing the need for patient-specific molecular analysis of the disease for choice of therapy. Figure 1 legend. (a) tSNE clustering of ~22,000 genes according to co-expression within a cohort of 522 primary MM samples, as per RNA-Seq (one black dot per gene). Blue disks represent genes from the mediator complex family, red disks represent super-enhancer regulated genes, and green disks are genes coding for transcription factors. (b) Clustergram representing Spearman correlation between expression of ~22,000 and ex vivo resistance to 43 different drugs. Red stands for direct correlation (high expression in resistance), green for inverse (low expression in resistance). (c and d) tSNE clustering of genes colored according to individual Spearman correlation between gene expression and resistance to ABT-199 and MK2206, respectively. Arrows point to clusters highest related to resistance. Figure 1. Figure 1. Disclosures No relevant conflicts of interest to declare.
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Lih, C., Y. Li, L. Trinh, S. Chien, X. Wu, W. Liu, and P. M. Williams. "Breast cancer patients stratification by microarray-based gene expression profiling from FFPET samples." Journal of Clinical Oncology 27, no. 15_suppl (May 20, 2009): e22041-e22041. http://dx.doi.org/10.1200/jco.2009.27.15_suppl.e22041.
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e22041 Background: Microarrays have been used to monitor global genes expression and have aided the identification of novel biomarkers for patients stratification and drug response prediction . To date there has been limited application of microarray- based gene expression analysis to formalin fixed paraffin embedded tissues (FFPET). FFPE tissues are the most commonly available clinical samples with documented clinical information for retrospective clinical analysis. However, FFPET RNA has proven to be an obstacle for microarray analysis because of low yield and compromised RNA integrity. Methods: Using a novel RNA amplification method, Single Primer Isothermal Amplification (SPIA, NuGEN Inc, San Carlos, CA), we amplified FFPET RNA, hybridized amplified, and labeled cDNA onto Affymetrix HG U133plus2 GeneChips. Results: We found that SPIA amplification successfully overcomes the problems of poor quality of FFPET RNA, and produced informative biological data. Comparing the gene expression data from 5 different types of FFPET archival cancer samples (breast, lung, ovarian, colon, and melanoma), we demonstrated that gene expression signatures clearly distinguish the tissue of origin. Further, from an analysis of 91 FFPET samples comprised of ER+, HER2+, triple negative breast cancer patients, and normal breast tissue, we have identified a 103 gene signature that distinguishes the intrinsic sub-types of breast cancer. Finally, the accuracy of gene expression measured by microarray was verified by real time PCR quantitation of the ERBB2 gene, resulting in a significant correlation (R = 0.88). Conclusions: We have demonstrated the feasibility of global gene expression profiling using RNA extracted from FFPET and have shown that a gene expression signature can stratify patient samples into different subtypes of disease. This study paves the way to identify novel molecular biomarkers for disease stratification and therapy response from archival FFPET samples, leading to the goals of personalized medicine. No significant financial relationships to disclose.
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Yan, Z., M. T. Hamilton, and F. W. Booth. "CYTOCHROME C GENE EXPRESSION AND RNA-PROTEIN INTERACTION IN STIMULATED RAT SKELETAL MUSCLE 452." Medicine & Science in Sports & Exercise 28, Supplement (May 1996): 76. http://dx.doi.org/10.1097/00005768-199605001-00452.
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Falsini, Sara, Emanuela Di Cola, Martin In, Maria Giordani, Stefano Borocci, and Sandra Ristori. "Complexation of short ds RNA/DNA oligonucleotides with Gemini micelles: a time resolved SAXS and computational study." Physical Chemistry Chemical Physics 19, no. 4 (2017): 3046–55. http://dx.doi.org/10.1039/c6cp06475b.
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Poddar, Arpita, Suneela Pyreddy, Francesco Carraro, Sudip Dhakal, Andrea Rassell, Matthew R. Field, T. Srinivasa Reddy, Paolo Falcaro, Cara M. Doherty, and Ravi Shukla. "ZIF-C for targeted RNA interference and CRISPR/Cas9 based gene editing in prostate cancer." Chemical Communications 56, no. 98 (2020): 15406–9. http://dx.doi.org/10.1039/d0cc06241c.
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Metal–organic-frameworks for gene therapy in prostate cancer – ZIF-C based delivery of RNA interference and CRISPR/Cas9 causes host gene expression knockdown. Coating with a green tea phytochemical enhances uptake and increases cancer cytotoxicity.
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Shinoura, Nobusada, Lin Chen, Maqsood A. Wani, Young Gyu Kim, Jeffrey J. Larson, Ronald E. Warnick, Matthias Simon, Anil G. Menon, Wan Li Bi, and Peter J. Stambrook. "Protein and messenger RNA expression of connexin43 in astrocytomas: implications in brain tumor gene therapy." Journal of Neurosurgery 84, no. 5 (May 1996): 839–45. http://dx.doi.org/10.3171/jns.1996.84.5.0839.
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✓ The expression of connexin43, the primary gap-junction constituent of glial cells, was evaluated at the messenger RNA and protein levels in different grades of astrocytoma to investigate the relevance of gap junctions in herpes simplex virus—thymidine kinase (HSV-tk)—mediated gene therapy of brain tumors. Transduction of the retroviral-mediated HSV-tk gene into tumor cells with subsequent administration of ganciclovir has recently been used as an experimental therapeutic strategy for treatment of brain tumors. One aspect of this approach is the bystander effect, which augments the efficacy of this therapeutic approach. Glioblastoma cells with minimum levels of connexin43 protein were transfected with a connexin43 complementary DNA. These cells manifested a marked increase in the in vitro bystander effect, supporting the contention that the in vitro bystander effect is a consequence of metabolic cooperation between cells mediated by gap junctions. To assess relative levels of gap-junction protein expression in the relevant tumor type, we examined primary astrocytomas, primary astrocytoma cell cultures, and glioblastoma cell lines. Although most astrocytoma tumor samples expressed connexin43, they differed in the level of expression, with the greatest variation exhibited in high-grade astrocytomas. Primary glioblastoma cell cultures and established glioblastoma cell lines also displayed some variability in connexin43 levels. In aggregate, our results anticipate that glioblastomas will have a varied bystander effect during HSV-tk gene therapy depending on the level of connexin43 expression.
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Sorokin, Maxim, Irina Kholodenko, Daniel Kalinovsky, Tatyana Shamanskaya, Igor Doronin, Dmitry Konovalov, Aleksei Mironov, et al. "RNA Sequencing-Based Identification of Ganglioside GD2-Positive Cancer Phenotype." Biomedicines 8, no. 6 (May 30, 2020): 142. http://dx.doi.org/10.3390/biomedicines8060142.
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The tumor-associated ganglioside GD2 represents an attractive target for cancer immunotherapy. GD2-positive tumors are more responsive to such targeted therapy, and new methods are needed for the screening of GD2 molecular tumor phenotypes. In this work, we built a gene expression-based binary classifier predicting the GD2-positive tumor phenotypes. To this end, we compared RNA sequencing data from human tumor biopsy material from experimental samples and public databases as well as from GD2-positive and GD2-negative cancer cell lines, for expression levels of genes encoding enzymes involved in ganglioside biosynthesis. We identified a 2-gene expression signature combining ganglioside synthase genes ST8SIA1 and B4GALNT1 that serves as a more efficient predictor of GD2-positive phenotype (Matthews Correlation Coefficient (MCC) 0.32, 0.88, and 0.98 in three independent comparisons) compared to the individual ganglioside biosynthesis genes (MCC 0.02–0.32, 0.1–0.75, and 0.04–1 for the same independent comparisons). No individual gene showed a higher MCC score than the expression signature MCC score in two or more comparisons. Our diagnostic approach can hopefully be applied for pan-cancer prediction of GD2 phenotypes using gene expression data.
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Bender, M. A., A. D. Miller, and R. E. Gelinas. "Expression of the human beta-globin gene after retroviral transfer into murine erythroleukemia cells and human BFU-E cells." Molecular and Cellular Biology 8, no. 4 (April 1988): 1725–35. http://dx.doi.org/10.1128/mcb.8.4.1725.
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Replication-defective amphotropic retrovirus vectors containing either the human beta-globin gene with introns or an intronless beta-globin minigene were constructed and used to study beta-globin expression following gene transfer into hematopoietic cells. The beta-globin genes were marked by introducing a 6-base-pair insertion into the region corresponding to the 5' untranslated region of the beta-globin mRNA to allow detection of RNA encoded by the new gene in human cells expressing normal human beta-globin RNA. Introduction of a virus containing the beta-globin gene with introns into murine erythroleukemia cells resulted in inducible expression of human beta-globin RNA and protein, while the viruses containing the minigene were inactive. The introduced human beta-globin gene was 6 to 110% as active as the endogenous mouse beta maj-globin genes in six randomly chosen cell clones. Introduction of the viruses into human BFU-E cells, followed by analysis of marked and unmarked globin RNAs in differentiated erythroid colonies, revealed that the introduced beta-globin gene was about 5% as active as the endogenous genes in these normal human erythroid cells and that again the minigene was inactive. These data are discussed in terms of the potential treatment of genetic disease by gene therapy.
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Bender, M. A., A. D. Miller, and R. E. Gelinas. "Expression of the human beta-globin gene after retroviral transfer into murine erythroleukemia cells and human BFU-E cells." Molecular and Cellular Biology 8, no. 4 (April 1988): 1725–35. http://dx.doi.org/10.1128/mcb.8.4.1725-1735.1988.
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Replication-defective amphotropic retrovirus vectors containing either the human beta-globin gene with introns or an intronless beta-globin minigene were constructed and used to study beta-globin expression following gene transfer into hematopoietic cells. The beta-globin genes were marked by introducing a 6-base-pair insertion into the region corresponding to the 5' untranslated region of the beta-globin mRNA to allow detection of RNA encoded by the new gene in human cells expressing normal human beta-globin RNA. Introduction of a virus containing the beta-globin gene with introns into murine erythroleukemia cells resulted in inducible expression of human beta-globin RNA and protein, while the viruses containing the minigene were inactive. The introduced human beta-globin gene was 6 to 110% as active as the endogenous mouse beta maj-globin genes in six randomly chosen cell clones. Introduction of the viruses into human BFU-E cells, followed by analysis of marked and unmarked globin RNAs in differentiated erythroid colonies, revealed that the introduced beta-globin gene was about 5% as active as the endogenous genes in these normal human erythroid cells and that again the minigene was inactive. These data are discussed in terms of the potential treatment of genetic disease by gene therapy.
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Tsuruta, Toshihisa, Hitoshi Kanno, Yasuo Aihara, Takako Hamada, Masako Sakauchi, Makiko Osawa, Emiko Wada, Osami Kubo, Tomokatsu Hori, and Hisaichi Fujii. "Target Marker Gene Expressions and the Possibility of Molecular Therapy for Children’s Brain Tumors." Blood 108, no. 11 (November 16, 2006): 5468. http://dx.doi.org/10.1182/blood.v108.11.5468.5468.
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Abstract ErbB2, c-Myc and p53 gene expressions are widely reported for the poor prognostic markers for medulloblastoma (MB) patients. Recently, Wnt pathway and Sonic Hedgehog (SHH) pathways are known to related to the oncogenesis of MB cells, and the PDGF receptor gene and some adhesion molecule gene expressions are also known to the markers of the dissemination or the metastasis of MB cells. For adult malignant brain tumors, the molecular targeted therapy of the antibody (trastuzumab, cetuximab), the tyrosine kinase inhibitor (imatinib, gefinitib) or other signal transduction inhibitor (cyclopamin) are clinically researched. We examined several important marker gene expressions of the molecular therapy in various children’s brain tumors and searched the possible molecular targeted therapy. [Materials and methods] Fifteen children’s brain tumor (five MB, seven glioma, three ependymoma) and four adult brain tumor (two glioma, two glioblastoma) were examind. The three MB cases were primary metaststic ones. The mRNA expressions of the marker genes (ErbB2, PDGF receptor, PCNA, SPARC, β-catenin, SUFU, c-Myc, p53, TrkC and so on) were examined by quantity polymerase chain (qPCR) reaction with fresh frozen tumor cells. For the normal control, we used the normal cerebellum total RNA samples of the Becton, Dikinson and Company. CYBR green coloring system was used for the qPCR and their primers were designed in the region between two exons. GAPDH gene expression was also examined as an internal control and all of the gene expression were normalized by GAPDH expression. [Results] ErbB2 gene expression in MB cells were various, but their expression were similar to clinical futures, such as, the higher expressed cases had some high risk factors. In glioma cells, ErbB2 gene expression were almost equal by lower levels. PDGF receptor gene expression were more than five to ten times elevated in all of the glioma cells, even if they were low grade malignancy glioma, and were higher than that in MB cells. PCNA was specially elevated in primary metastatic MB cells. [Conclusion] Our data shows that the molecular characteristics of the children’s brain tumors were thought to be different by cases, even if they had same histopathological characters. Some special gene tageting therapy, such as anti-ErbB2, PDGFR and/or PCNA therapy can be used for the various children’s brain tumors which are resistant for conventional therapies and are cured by adequate molecular therapy.
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Lanceta, Lilibeth, Nadiia Lypova, Conor O’Neill, Xiaohong Li, Eric Rouchka, Jason Chesney, and Yoannis Imbert-Fernandez. "Differential gene expression analysis of palbociclib-resistant TNBC via RNA-seq." Breast Cancer Research and Treatment 186, no. 3 (February 18, 2021): 677–86. http://dx.doi.org/10.1007/s10549-021-06127-5.
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Abstract Purpose The management of triple-negative breast cancer (TNBC) remains a significant clinical challenge due to the lack of effective targeted therapies. Inhibitors of the cyclin-dependent kinases 4 and 6 (CDK4/6) are emerging as promising therapeutic agents against TNBC; however, cells can rapidly acquire resistance through multiple mechanisms that are yet to be identified. Therefore, determining the mechanisms underlying resistance to CDK4/6 inhibition is crucial to develop combination therapies that can extend the efficacy of the CDK4/6 inhibitors or delay resistance. This study aims to identify differentially expressed genes (DEG) associated with acquired resistance to palbociclib in ER− breast cancer cells. Methods We performed next-generation transcriptomic sequencing (RNA-seq) and pathway analysis in ER− MDA-MB-231 palbociclib-sensitive (231/pS) and palbociclib-resistant (231/pR) cells. Results We identified 2247 up-regulated and 1427 down-regulated transcripts in 231/pR compared to 231/pS cells. DEGs were subjected to functional analysis using Gene Ontology (GO) and the KEGG database which identified many transduction pathways associated with breast cancer, including the PI3K/AKT, PTEN and mTOR pathways. Additionally, Ingenuity Pathway Analysis (IPA) revealed that resistance to palbociclib is closely associated with altered cholesterol and fatty acid biosynthesis suggesting that resistance to palbociclib may be dependent on lipid metabolic reprograming. Conclusion This study provides evidence that lipid metabolism is altered in TNBC with acquired resistance to palbociclib. Further studies are needed to determine if the observed lipid metabolic rewiring can be exploited to overcome therapy resistance in TNBC.
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Su, Chun Nian, and Min Yu. "Specifically Deoxyribozyme of the PTPRO Gene as a Potential Gene Therapy Means for Human Hepatocellular Carcinoma." Advanced Materials Research 781-784 (September 2013): 1203–8. http://dx.doi.org/10.4028/www.scientific.net/amr.781-784.1203.
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Protein tyrosine phosphatase receptor-type O (PTPRO) has been described in several forms of cancer as a new member of the PTP family. The tumor suppressor function of PTPRO was evaluated by design and synthesis the 10-23 deoxyribozyme (DRz), thio-modified DRz (DRz-s) and antisense oligonucleotide (asON) of the PTPRO genomic mRNA to detect the catalytic cleavage activity. Firstly, the cDNA fragment of PTPRO gene was amplified from total cellular RNA of the HepG2.2.15 cells by reverse transcription PCR (RT-PCR). Subsequently, the fragments were cloned to pcDNA3.1(+) plasmids and generated a recombinant plasmids, then sifted the positive recombinant plasmids out to amplify. The expression vector of PTPRO mRNA was obtained in vitro transcription by using T7 RNA polymerase. The results of transfection indicated that when PTPRO mRNA gamyed with deoxyribozyme which activity enhanced, so DRz-s were detected with more intensive specific catalytic cleavage activity than DRz by cells transfecting. And the asON wasn't detected with the property.
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Agahozo, Marie Colombe, Marcel Smid, Ronald van Marion, Dora Hammerl, Thierry P. P. van den Bosch, Mieke A. M. Timmermans, Chayenne J. Heijerman, et al. "Transcriptomic Properties of HER2+ Ductal Carcinoma In Situ of the Breast Associate with Absence of Immune Cells." Biology 10, no. 8 (August 12, 2021): 768. http://dx.doi.org/10.3390/biology10080768.
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The identification of transcriptomic alterations of HER2+ ductal carcinoma in situ (DCIS) that are associated with the density of tumor-infiltrating lymphocytes (TILs) could contribute to optimizing choices regarding the potential benefit of immune therapy. We compared the gene expression profile of TIL-poor HER2+ DCIS to that of TIL-rich HER2+ DCIS. Tumor cells from 11 TIL-rich and 12 TIL-poor DCIS cases were micro-dissected for RNA isolation. The Ion AmpliSeq Transcriptome Human Gene Expression Kit was used for RNA sequencing. After normalization, a Mann–Whitney rank sum test was used to analyze differentially expressed genes between TIL-poor and TIL-rich HER2+ DCIS. Whole tissue sections were immunostained for validation of protein expression. We identified a 29-gene expression profile that differentiated TIL-rich from TIL-poor HER2+ DCIS. These genes included CCND3, DUSP10 and RAP1GAP, which were previously described in breast cancer and cancer immunity and were more highly expressed in TIL-rich DCIS. Using immunohistochemistry, we found lower protein expression in TIL-rich DCIS. This suggests regulation of protein expression at the posttranslational level. We identified a gene expression profile of HER2+ DCIS cells that was associated with the density of TILs. This classifier may guide towards more rationalized choices regarding immune-mediated therapy in HER2+ DCIS, such as targeted vaccine therapy.
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Zheng, Bin, QingYun Mai, JinXing Jiang, and QinQin Zhou. "The Therapeutic Potential of Small Activating RNAs for Colorectal Carcinoma." Current Gene Therapy 19, no. 3 (September 18, 2019): 140–46. http://dx.doi.org/10.2174/1566523219666190708111404.
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Small double-strand RNAs have been recognized as master regulators of gene expression. In contrast to the evolutionary conserved RNA interference machinery, which degrades or inhibits the translation of target mRNAs, small activating RNA (saRNA) activates the specific gene in a target dependent manner through a similar mechanism as RNAi. Recently, saRNA mediated expression regulation of specific genes has been extensively studied in cancer researches. Of particular interest is the application of the RNA mediated gene activation within colorectal cancer (CRC) development, due to the high incidence of the CRC. In this review, we summarize the current knowledge of saRNA mediated genetic activation and its underlying mechanisms. Furthermore, we highlight the advantages of the utilization of saRNAs induced gene expression as an investigating tool in colorectal cancer research. Finally, the possibility and the challenge of the saRNA application as a potential therapy for colorectal cancer are addressed.
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Sugasawa, Takehito, Takuro Nakano, Shin-ichiro Fujita, Yuki Matsumoto, Genki Ishihara, Kai Aoki, Koki Yanazawa, et al. "Proof of Gene Doping in a Mouse Model with a Human Erythropoietin Gene Transferred Using an Adenoviral Vector." Genes 12, no. 8 (August 16, 2021): 1249. http://dx.doi.org/10.3390/genes12081249.
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Despite the World Anti-Doping Agency (WADA) ban on gene doping in the context of advancements in gene therapy, the risk of EPO gene-based doping among athletes is still present. To address this and similar risks, gene-doping tests are being developed in doping control laboratories worldwide. In this regard, the present study was performed with two objectives: to develop a robust gene-doping mouse model with the human EPO gene (hEPO) transferred using recombinant adenovirus (rAdV) as a vector and to develop a detection method to identify gene doping by using this model. The rAdV including the hEPO gene was injected intravenously to transfer the gene to the liver. After injection, the mice showed significantly increased whole-blood red blood cell counts and increased expression of hematopoietic marker genes in the spleen, indicating successful development of the gene-doping model. Next, direct and potentially indirect proof of gene doping were evaluated in whole-blood DNA and RNA by using a quantitative PCR assay and RNA sequencing. Proof of doping could be detected in DNA and RNA samples from one drop of whole blood for approximately a month; furthermore, the overall RNA expression profiles showed significant changes, allowing advanced detection of hEPO gene doping.
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Lundstrom, Kenneth. "Alphavirus Vectors as Tools in Cancer Gene Therapy." Technology in Cancer Research & Treatment 1, no. 1 (February 2002): 83–88. http://dx.doi.org/10.1177/153303460200100111.
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Alphavirus vectors, particularly those based on the replicon of Semliki Forest virus, have shown great potential as gene delivery vehicles for various applications in cancer gene therapy. The rapid production of high-titer recombinant SFV particles, which show impressive transduction rates in various mammalian cell lines, primary cultures and in vivo, results in high levels of transgene expression. Additionally, SFV vectors induce apoptosis in transduced host cells, which can further increase their efficiency in tumor therapy. Because of the broad host range some attempts to target the gene delivery have been engineered for Sindbis virus vectors, where IgG binding domains of protein A have been introduced into the envelope structure of the recombinant particles to allow attachment of virus to host cells through the interaction of protein A with monoclonal antibodies. SFV vectors have also been employed for the production of retrovirus-like particles for establishment of long-term gene expression. Tumor vaccine approaches have been taken by injection of SFV vectors as naked RNA molecules, DNA plasmids or recombinant particles to achieve both therapeutic and prophylactic efficacy. The continuous improvement of alphavirus vectors will further expand the application range in the future.
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Zhang, Jing, Osamu Yamada, Takashi Sakamoto, Hiroshi Yoshida, Hiromasa Araki, and Kunitada Shimotohno. "Exploiting cis-Acting Replication Elements To Direct Hepatitis C Virus-Dependent Transgene Expression." Journal of Virology 79, no. 10 (May 15, 2005): 5923–32. http://dx.doi.org/10.1128/jvi.79.10.5923-5932.2005.
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ABSTRACT We describe here a novel targeting gene therapy strategy to direct gene expression responsive to hepatitis C virus (HCV). The goal was approached by engineering a construct containing the antisense sequence of the transgene and internal ribosome entry site of encephalomyocarditis virus flanked by 5′- and 3′-end sequences of HCV cDNA that contain cis-acting replication elements. Thus, expression of the transgene is only promoted when the minus-strand RNA has been synthesized by the functional replication machinery present in infected cells. Reporter assay and strand-specific reverse transcription-PCR showed selective transgene expression in Huh-7 cells harboring an autonomously replicating HCV subgenome but remaining silent in uninfected cells. Furthermore, using the cytosine deaminase suicide gene as a transgene coupled with recombinant adenovirus delivery, we demonstrated that cytosine deaminase was specifically expressed in replicon cells, resulting in marked chemosensitization of replicon cells to the cytotoxic effects of flucytosine. This new targeting strategy could be extended to other single-stranded RNA viruses encoding the unique RNA-dependent RNA polymerase that has no parallel in mammalian cells.
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Schulze, M., M. Hlevnjak, V. Thewes, S. Elgaafary, A. Mavratzas, S. Fröhling, J. Seitz, M. Zapatka, P. Lichter, and A. Schneeweiss. "Improving personalised therapy in metastatic breast cancer by implementing RNA sequencing based gene expression signatures." Annals of Oncology 30 (November 2019): vii21. http://dx.doi.org/10.1093/annonc/mdz413.074.
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Hashemi, Atieh, and Gilar Gorji-bahri. "MicroRNA: Promising Roles in Cancer Therapy." Current Pharmaceutical Biotechnology 21, no. 12 (October 22, 2020): 1186–203. http://dx.doi.org/10.2174/1389201021666200420101613.
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MicroRNAs (miRNA) are small non-coding RNAs that act as one of the main regulators of gene expression. They are involved in maintaining a proper balance of diverse processes, including differentiation, proliferation, and cell death in normal cells. Cancer biology can also be affected by these molecules by modulating the expression of oncogenes or tumor suppressor genes. Thus, miRNA based anticancer therapy is currently being developed either alone or in combination with chemotherapy agents used in cancer management, aiming at promoting tumor regression and increasing cure rate. Access to large quantities of RNA agents can facilitate RNA research and development. In addition to currently used in vitro methods, fermentation-based approaches have recently been developed, which can cost‐effectively produce biological RNA agents with proper folding needed for the development of RNA-based therapeutics. Nevertheless, a major challenge in translating preclinical studies to clinical for miRNA-based cancer therapy is the efficient delivery of these agents to target cells. Targeting miRNAs/anti-miRNAs using antibodies and/or peptides can minimize cellular and systemic toxicity. Here, we provide a brief review of miRNA in the following aspects: biogenesis and mechanism of action of miRNAs, the role of miRNAs in cancer as tumor suppressors or oncogenes, the potential of using miRNAs as novel and promising therapeutics, miRNA-mediated chemo-sensitization, and currently utilized methods for the in vitro and in vivo production of RNA agents. Finally, an update on the viral and non-viral delivery systems is addressed.
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Pushkin, Anton, Oleg I. Kit, Eduard Evgenevich Rostorguev, David H. Porksheyan, Natalya S. Kuznetsova, and Sergey E. Kavitskiy. "Aberrant miRNA expression in glioma." Journal of Clinical Oncology 37, no. 15_suppl (May 20, 2019): e13506-e13506. http://dx.doi.org/10.1200/jco.2019.37.15_suppl.e13506.
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e13506 Background: Gliomas are the most common type of primary brain tumors, with a high level of recurrence and mortality. The purpose of the study was to determine the expression profile of micro-RNA targeting components of the Hedgehog, Notch, Wnt, EGFR, TGFβ, HIF1α signaling pathways according to MirTarBase, miRDB, TargetScan. Methods: The study included 30 patients (15 women and 15 men) aged 27 to 76 years with histologically verified glial brain tumors. The RT2-qPCR method in operational biopsy specimens determined the relative expression of 12 micro-RNAs: hsa-miR-17-3p, hsa-miR-20a-3p, hsa-miR-326, hsa-miR-330-3p, hsa-miR- 107, hsa-miR-143-3p, hsa-let-7a-5p, hsa-miR-146a-5p, hsa-miR-29a-3p, hsa-miR-92a-1-5p, hsa-miR-26b-3p, hsa-miR-96-5p. Hsa-miR-7-5p and hsa-miR-126-3p were used as reference micro-RNA. Results: A statistically significant increase in the expression of hsa-miR-143-3p, hsa-miR-146a-5p and hsa-miR-92a-1-5p by 2, 2.2 and 2.9 times, respectively, was found, as well as a decrease in the expression of hsa-miR-330- 3p by 4.1 times in tumor tissue of the brain relative to normal tissue (p < 0.05). Reduced expression of micro-RNA hsa-miR-330-3p may increase the activity of the VEGFA gene, which leads to intensive vascularization of the tumor. In addition, hsa-miR-330-3p is a validated negative regulator of the E2F1 gene known as a regulator of the cell cycle and tumor suppressor proteins. The TRAF6 gene is the direct validated target of hsa-miR-146a-5p, and its overexpression is associated with the patient's chemoresistance to temozolomide. Increased hsa-miR-143-3p micro-RNA expression can reduce the activity of the EGLN1 gene that also mediates the adaptation of tumor cells to hypoxic conditions. Hsa-miR-92a-1-5p micro-RNA is a negative regulator of PTEN gene expression. Conclusions: A significant decrease in hsa-miR-330-3p expression and an increase in hsa-miR-146a-5p, hsa-miR-143-3p, and hsa-miR-92a-1-5p, which was found in gliomas, can potentially be used to develop prognostic markers and therapeutic targets for targeted therapy.
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Li, Hai-Ou, Ya-Feng Zhu, Makoto Asakawa, Hidekazu Kuma, Takahiro Hirata, Yasuji Ueda, Yun-Sik Lee, et al. "A Cytoplasmic RNA Vector Derived from Nontransmissible Sendai Virus with Efficient Gene Transfer and Expression." Journal of Virology 74, no. 14 (July 15, 2000): 6564–69. http://dx.doi.org/10.1128/jvi.74.14.6564-6569.2000.
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ABSTRACT We have recovered a virion from defective cDNA of Sendai virus (SeV) that is capable of self-replication but incapable of transmissible-virion production. This virion delivers and expresses foreign genes in infected cells, and this is the first report of a gene expression vector derived from a defective viral genome of theParamyxoviridae. First, functional ribonucleoprotein complexes (RNPs) were recovered from SeV cloned cDNA defective in the F (envelope fusion protein) gene, in the presence of plasmids expressing nucleocapsid protein and viral RNA polymerase. Then the RNPs were transfected to the cells inducibly expressing F protein. Virion-like particles thus obtained had a titer of 0.5 × 108 to 1.0 × 108 cell infectious units/ml and contained F-defective RNA genome. This defective vector amplified specifically in an F-expressing packaging cell line in a trypsin-dependent manner but did not spread to F-nonexpressing cells. This vector infected and expressed an enhanced green fluorescent protein reporter gene in various types of animal and human cells, including nondividing cells, with high efficiency. These results suggest that this vector has great potential for use in human gene therapy and vaccine delivery systems.
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Bofill, Salvador, Carmen Garrigos, Marta Benavent, Rosario Gonzalez, Alvaro Montaño, and Alejandro Falcon Gonzalez. "Gene expression profiling involved in response to neoadjuvant therapy in breast cancer." Journal of Clinical Oncology 38, no. 15_suppl (May 20, 2020): e12618-e12618. http://dx.doi.org/10.1200/jco.2020.38.15_suppl.e12618.
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e12618 Background: Neoadjuvant systemic therapy for breast cancer is used increasingly but, there is a group of patients which do not benefit from this therapy. With these premises, we stablished that our main objective was to identify differential expression genes patterns in patients (pts) with the ER/PR- Her2+, ER/PR+ Her2+ and triple negative (TN) subtypes breast cancers according to response to neoadjuvant therapy. Methods: RNA from formalin fixed paraffin embedded tumor samples from 54 pts with breast cancer that had received neoadjuvant therapy was extracted with mirVana miRNA isolation kit (Ambion). Patients with TN subtype received neoadjuvant chemotherapy based on anthracyclines and taxanes and patients with the Her2+ subtype received treatment with taxanos-trastuzumab and anthracyclines. The RNA expression levels were identified by ClariomD Asssay (ThermoFisher). Results were analyzed with Transcriptome Analysis Console and with in-house scripts in R (version 3.5.1). Data were corrected and normalized using Robust Multichip Average method from the oligo package. Expression was summarized at gene level using the corresponding annotation for ClariomD array BrainArray. Expression analyses were performed with limma package. A fold change ≥ 2 and p < 0.05 was considered statistically significant. We defined to groups: R (response, RCB 0) and NR (not response, RCB III) pts. Results: The median age of the pts was 52 years and 58% were menopausal and 42% pre-menopausal. Tumor stage were T1 9%, T2 50%, T3 30%, T4 11% and lymph node involvement were N0 31%, N1 41%, N2 24%, N3 4%. We obtained twelve genes differentially expressed in R vs NR groups. Respect to TN, two genes (AC053503.12, C9orf153) were differentially expressed between R (n = 11) and NR (n = 11). In ER/PR+ Her2+ subgroup, NBPF4 showed a differential expression in R (n = 8) vs NR (n = 7). In pts with ER/PR- Her2+, nine genes (DHRS2, SLCO1B3, UGT2B15, RGS2, SULT1E1, MED23, FKBP5, MIEN1, HER2) were differentially expressed in R (n = 10) vs NR (n = 7). We have started a validation in an independent cohort of pts in ER/PR+ Her2+ subgroup, confirming the results previously obtained. Conclusions: We found twelve genes differentially expressed in the different molecular subtypes of breast cancer involved in the response to neoadjuvant therapy. Several of these genes, especially UGT2B15, SULT1E1, FKBP5, MIEN1 and HER2 have been reported as key genes in tumoral processes, such as cell proliferation, invasion and drug resistant pathways, suggesting that its could be good biomarkers of response to neoadjuvant therapy in breast cancer.
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Poddubskaya, Elena, Maxim Sorokin, Andrew Garazha, Alex Glusker, Alexey Moisseev, Marina Sekacheva, Maria Suntsova, et al. "Clinical use of RNA sequencing and oncobox analytics to predict personalized targeted therapeutic efficacy." Journal of Clinical Oncology 38, no. 15_suppl (May 20, 2020): e13676-e13676. http://dx.doi.org/10.1200/jco.2020.38.15_suppl.e13676.
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e13676 Background: Analysis of mutation profiles in cancer patients does not provide clinical benefits in 80-90% of cases in the US (Marquart et al., 2018). Gene expression analysis potentially complements standard detection of clinically relevant mutations. Methods: 239 adult late-stage cancer patients. RNA gene expression sequencing completed on solid tumor samples using FFPE blocks. Patient mRNA profiles were analyzed using Oncobox bioinformatics, prioritizing target drugs according to their personalized predicted efficacy. Summary reports were provided to oncologists and resulting treatment selection and outcomes were assessed. Results: As of February 2020, feedback was received from participating doctors for 224 patients; 34 patients died before therapy prescription, 52 patients received treatment other than targeted therapy (chemo, surgery, radiation, or palliative care), 75 patients received at least one targeted therapy (single or combination therapy) predicted to be effective based on Oncobox analysis (“RNAseq cohort”). 63 patients received chemo or other drug therapy predicted to be potentially ineffective from Oncobox analysis (“other cohort”). Therapeutic response was obtained on 46 patients with biopsies collected no longer than 6 months prior to analysis who had no further surgery (30 in the RNAseq cohort and 16 in the other cohort). 63% of the RNAseq cohort obtained either partial response or stable disease using Oncobox guided therapies, compared to 44% of the other cohort (19% increase of disease control). The RNAseq cohort had higher mean prior therapies (1.3) compared to the other cohort (0.8) indicating more advanced disease. The similarly designed WINTHER trial reported ~8% increase of disease control using gene expression-guided vs mutation-guided therapeutics in a cohort of advanced cancer patients averaging three prior therapies (Rodon et al., 2019). Conclusions: Collectively these data suggest that gene expression profiling provides a more clinically relevant therapeutic match, and better response rates, than mutation guided therapeutic treatments. This potentially results in improved clinical outcomes for cancer patients. Clinical trial information: NCT03724097.
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Lundstrom, Kenneth. "Self-Replicating RNA Viruses for RNA Therapeutics." Molecules 23, no. 12 (December 13, 2018): 3310. http://dx.doi.org/10.3390/molecules23123310.
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Self-replicating single-stranded RNA viruses such as alphaviruses, flaviviruses, measles viruses, and rhabdoviruses provide efficient delivery and high-level expression of therapeutic genes due to their high capacity of RNA replication. This has contributed to novel approaches for therapeutic applications including vaccine development and gene therapy-based immunotherapy. Numerous studies in animal tumor models have demonstrated that self-replicating RNA viral vectors can generate antibody responses against infectious agents and tumor cells. Moreover, protection against challenges with pathogenic Ebola virus was obtained in primates immunized with alphaviruses and flaviviruses. Similarly, vaccinated animals have been demonstrated to withstand challenges with lethal doses of tumor cells. Furthermore, clinical trials have been conducted for several indications with self-amplifying RNA viruses. In this context, alphaviruses have been subjected to phase I clinical trials for a cytomegalovirus vaccine generating neutralizing antibodies in healthy volunteers, and for antigen delivery to dendritic cells providing clinically relevant antibody responses in cancer patients, respectively. Likewise, rhabdovirus particles have been subjected to phase I/II clinical trials showing good safety and immunogenicity against Ebola virus. Rhabdoviruses have generated promising results in phase III trials against Ebola virus. The purpose of this review is to summarize the achievements of using self-replicating RNA viruses for RNA therapy based on preclinical animal studies and clinical trials in humans.
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Wahane, Aniket, Akaash Waghmode, Alexander Kapphahn, Karishma Dhuri, Anisha Gupta, and Raman Bahal. "Role of Lipid-Based and Polymer-Based Non-Viral Vectors in Nucleic Acid Delivery for Next-Generation Gene Therapy." Molecules 25, no. 12 (June 22, 2020): 2866. http://dx.doi.org/10.3390/molecules25122866.
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The field of gene therapy has experienced an insurgence of attention for its widespread ability to regulate gene expression by targeting genomic DNA, messenger RNA, microRNA, and short-interfering RNA for treating malignant and non-malignant disorders. Numerous nucleic acid analogs have been developed to target coding or non-coding sequences of the human genome for gene regulation. However, broader clinical applications of nucleic acid analogs have been limited due to their poor cell or organ-specific delivery. To resolve these issues, non-viral vectors based on nanoparticles, liposomes, and polyplexes have been developed to date. This review is centered on non-viral vectors mainly comprising of cationic lipids and polymers for nucleic acid-based delivery for numerous gene therapy-based applications.
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Gertz, Jay, Craig Rush, Jeffery Vahrenkamp, Kathryn Szczotka, Mark Dodson, Elke Jarboe, and Andrew Soisson. "Identification of Genes and Pathways Differentially Expressed in Progestin Responsive Endometrial Cancer and Hyperplasia." Journal of the Endocrine Society 5, Supplement_1 (May 1, 2021): A982. http://dx.doi.org/10.1210/jendso/bvab048.2008.
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Abstract One of the oldest and most common therapies for endometrial complex atypical hyperplasia (CAH) and low-stage, low-grade endometrioid endometrial carcinoma (EEC) is the use of progestins. Importantly, the use of progestins remains the only fertility-sparing treatment available. Despite frequent initial response to progestins, relapse rates are high (35-50%). Currently, there are no biomarkers available for predicting a woman’s likelihood of successful progestin therapy. Primary samples (n = 63) were obtained from a total of 31 patients with either CAH or EEC who underwent progestin therapy and were acquired pre- and post-treatment with progestins. Pathological review of the FFPE samples was performed to identify regions of high hyperplastic or neoplastic content for core punches and RNA extraction. RNA-seq was then performed on the FFPE RNA using the TruSeq RNA Exome approach, a method that uses targeted capture to improve sequencing from fragmented samples. Differential expression analysis was performed using two methods: DESeq2 a parametric method and Noiseq a non-parametric method. Both methods were used to obtain an overlapping subset of genes to reduce spurious results due to samples with outlier expression. Analysis of all samples identified 137 genes significantly associated with outcome. These 137 genes were largely increased in post-treatment samples from progestin responders and were highly enriched for progestogen and estrogen responsive genes, indicating a strong hormonal gene expression response to progestin therapy. Importantly, post-treatment samples from non-responding patients did not show this expression pattern, demonstrating that this set of genes may indicate successful hormone response in post-treatment samples. We also identified a 61 gene signature that remains high in non-responders after treatment compared to responders. Overall, we find that responders show a coordinated change in expression during progestin therapy that is missing from non-responders and this signature could be used in the early evaluation of progestin treatment success. Focusing solely on pre-treatment samples, we identified more variable expression differences across tumors, suggesting multiple reasons for progestin success/failure. We found that the combined expression of estrogen receptor alpha and progesterone receptor was predictive of progestin therapy success. In addition, non-responding tumors had increased expression of several immune-related genes that we are currently exploring. Overall, these results show that progestin therapy response could be predicted using gene expression signatures and that multiple factors may underlie progestin success/failure.
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Tsumagari, Koji, Patrick Miller, Marcus Marie Moses, Elisa Ledet, and A. Oliver Sartor. "Initial whole blood-based gene expression profile assays in mCRPC pts." Journal of Clinical Oncology 36, no. 6_suppl (February 20, 2018): 370. http://dx.doi.org/10.1200/jco.2018.36.6_suppl.370.
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370 Background: Although second generation androgen receptor (AR) targeting therapy, abiraterone (Abi) and enzalutamide (enza), improve therapeutic effect for patients of mCRPC, acquired resistance occurs. Biomarkers are clearly needed to predict the efficacy of AR targeting drugs for mCRPC patients and much work is occurring on this important issue. Circulating tumor cells are attractive biomaterials because of non-invasive collecting methods. In this study, we assessed whole blood RNA as a non-invasive methodology to access biomarkers of potential interest. Methods: We used whole blood (~5mL) preserved in PAXgene tubes from 10 patients (pts) with mCRPC with acquired resistance following Abi and 11 controls without prostate cancer. Total RNA was extracted followed by qRT-PCR for assessment of 10 transcripts including ARV7, HOXB13, GHLR2, KLK3, KLK2, FOXA1, SchLAP1, KIF2C, MIA, and NCAM1. All amplicons were normalized to β-actin. Results: ARV7 (2/10), GRHL2 (2/10), HOXB13 (4/10), KLK3 (7/10), and KLK2 (4/10) amplicons were detected only in the mCRPC prostate pts. FOXA1 (7/10) and SchLAP1 (3/10) amplicons were detected in mCRPC pts at higher concentrations in mCRPC pts as compared to controls ( p< 0.001 and p = 0.02, respectively). In contrast, KIF2C (5/11), MIA (11/11), and NCAM1 (11/11) amplicons were present in pts but in lower concentrations in mCRPC as compared to controls (p = 0.03, p< 0.001, and p< 0.001, respectively). Conclusions: We identified 5 transcripts that can be detected from whole blood RNA assays only from PCa pts, additional transcripts were expressed at higher or lower concentrations as compared to controls. Although this is a small cohort, these findings highlight the potential role for whole blood RNA to assess mCRPC pts.
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Strati, Areti, Michail Nikolaou, Vassilis Georgoulias, and Evi S. Lianidou. "RNA-Based CTC Analysis Provides Prognostic Information in Metastatic Breast Cancer." Diagnostics 11, no. 3 (March 14, 2021): 513. http://dx.doi.org/10.3390/diagnostics11030513.
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In metastatic breast cancer (MBC) the molecular characterization of circulating tumor cells (CTCs) provides a unique tool to understand metastasis-biology and therapy-resistance. We evaluated the prognostic significance of gene expression in EpCAM(+) CTCs in 46 MBC patients based on a long follow-up. We selected a panel consisting of stem cell markers (CD24, CD44, ALDH1), the mesenchymal marker TWIST1, receptors (ESR1, PGR, HER2, EGFR) and the epithelial marker CK-19. Singleplex RT-qPCR was used for TWIST1 and CK-19 and multiplex RT-qPCR for stem cell markers and receptors. A group of 19 healthy donors (HD) was used as control. Univariate (p = 0.001) and multivariate analysis (p = 0.002) revealed the prognostic value of combined gene expression of CK-19(+), CD44high/CD24low, ALDH1high/CD24low and HER2 over-expression for overall survival (OS). The Kaplan–Meier estimates of OS were significantly different in patients positive for CK-19 (p = 0.028), CD44high/CD24low (p = 0.002), ALDH1high/CD24low (p = 0.007) and HER2-positive (p = 0.022). Our results indicate that combined gene expression analysis in EpCAM(+) CTCs provides prognostic information in MBC.
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Arlen, Philip A., David G. Brooks, Lian Y. Gao, Dimitrios Vatakis, Helen J. Brown, and Jerome A. Zack. "Rapid Expression of Human Immunodeficiency Virus following Activation of Latently Infected Cells." Journal of Virology 80, no. 3 (February 1, 2006): 1599–603. http://dx.doi.org/10.1128/jvi.80.3.1599-1603.2006.
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ABSTRACT The host cell activation state impacts the nature of human immunodeficiency virus infection. Activated cells facilitate productive infections; quiescent cells enable the virus to enter a latent state, the major obstacle to viral clearance. We wanted to understand how these differences affected viral gene expression. In quiescent cells activated prior to infection, viral RNA was seen 12 h postinfection; when cells were stimulated postinfection, viral RNA was not seen until 36 h postinfection. Up-regulation of viral RNA in latently infected cells occurred within 2 h poststimulation. This hierarchy also held true for viral protein production. These results may explain the rapid reemergence of viremia following termination of therapy.