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https://www.readbyqxmd.com/read/28346378/dna-repair-pathway-alterations-in-bladder-cancer
#1
REVIEW
Kent W Mouw
Most bladder tumors have complex genomes characterized by a high mutation burden as well as frequent copy number alterations and chromosomal rearrangements. Alterations in DNA repair pathways-including the double-strand break (DSB) and nucleotide excision repair (NER) pathways-are present in bladder tumors and may contribute to genomic instability and drive the tumor phenotype. DNA damaging such as cisplatin, mitomycin C, and radiation are commonly used in the treatment of muscle-invasive or metastatic bladder cancer, and several recent studies have linked specific DNA repair pathway defects with sensitivity to DNA damaging-based therapy...
March 27, 2017: Cancers
https://www.readbyqxmd.com/read/28345004/homology-directed-recombination-for-enhanced-engineering-of-chimeric-antigen-receptor-t-cells
#2
Malika Hale, Baeckseung Lee, Yuchi Honaker, Wai-Hang Leung, Alexandra E Grier, Holly M Jacobs, Karen Sommer, Jaya Sahni, Shaun W Jackson, Andrew M Scharenberg, Alexander Astrakhan, David J Rawlings
Gene editing by homology-directed recombination (HDR) can be used to couple delivery of a therapeutic gene cassette with targeted genomic modifications to generate engineered human T cells with clinically useful profiles. Here, we explore the functionality of therapeutic cassettes delivered by these means and test the flexibility of this approach to clinically relevant alleles. Because CCR5-negative T cells are resistant to HIV-1 infection, CCR5-negative anti-CD19 chimeric antigen receptor (CAR) T cells could be used to treat patients with HIV-associated B cell malignancies...
March 17, 2017: Molecular Therapy. Methods & Clinical Development
https://www.readbyqxmd.com/read/28345000/syngeneic-aav-pseudo-particles-potentiate-gene-transduction-of-aav-vectors
#3
Qizhao Wang, Biao Dong, Katie A Pokiniewski, Jenni Firrman, Zhongren Wu, Mario P S Chin, Xiongwen Chen, LinShu Liu, Ruian Xu, Yong Diao, Weidong Xiao
Adeno-associated virus (AAV) vectors have emerged as a safe and efficient gene therapy platform. One complication is that a significant amount of empty particles have always been generated as impurities during AAV vector production. However, the effects of such particles on AAV vector performance remain unclear. Here we systemically evaluated the biological properties of three types of "empty" AAV particles: syngeneic pseudo-vectors with partial AAV genomes derived from DNA of the corresponding full particles, allogeneic pseudo-vectors with partial genomes different from the corresponding full particles, and null pseudo-vectors with no DNA inside the capsids...
March 17, 2017: Molecular Therapy. Methods & Clinical Development
https://www.readbyqxmd.com/read/28344998/low-dose-liver-targeted-gene-therapy-for-pompe-disease-enhances-therapeutic-efficacy-of-ert-via-immune-tolerance-induction
#4
Sang-Oh Han, Giuseppe Ronzitti, Benjamin Arnson, Christian Leborgne, Songtao Li, Federico Mingozzi, Dwight Koeberl
Pompe disease results from acid α-glucosidase (GAA) deficiency, and enzyme replacement therapy (ERT) with recombinant human (rh) GAA has clinical benefits, although its limitations include the short half-life of GAA and the formation of antibody responses. The present study compared the efficacy of ERT against gene transfer with an adeno-associated viral (AAV) vector containing a liver-specific promoter. GAA knockout (KO) mice were administered either a weekly injection of rhGAA (20 mg/kg) or a single injection of AAV2/8-LSPhGAA (8 × 10(11) vector genomes [vg]/kg)...
March 17, 2017: Molecular Therapy. Methods & Clinical Development
https://www.readbyqxmd.com/read/28344992/mechanism-of-deletion-removing-all-dystrophin-exons-in-a-canine-model-for-dmd-implicates-concerted-evolution-of-x-chromosome-pseudogenes
#5
D Jake VanBelzen, Alock S Malik, Paula S Henthorn, Joe N Kornegay, Hansell H Stedman
Duchenne muscular dystrophy (DMD) is a lethal, X-linked, muscle-wasting disorder caused by mutations in the large, 2.4-Mb dystrophin gene. The majority of DMD-causing mutations are sporadic, multi-exon, frameshifting deletions, with the potential for variable immunological tolerance to the dystrophin protein from patient to patient. While systemic gene therapy holds promise in the treatment of DMD, immune responses to vectors and transgenes must first be rigorously evaluated in informative preclinical models to ensure patient safety...
March 17, 2017: Molecular Therapy. Methods & Clinical Development
https://www.readbyqxmd.com/read/28344990/inspiired-a-pipeline-for-quantitative-analysis-of-sites-of-new-dna-integration-in-cellular-genomes
#6
Eric Sherman, Christopher Nobles, Charles C Berry, Emmanuelle Six, Yinghua Wu, Anatoly Dryga, Nirav Malani, Frances Male, Shantan Reddy, Aubrey Bailey, Kyle Bittinger, John K Everett, Laure Caccavelli, Mary J Drake, Paul Bates, Salima Hacein-Bey-Abina, Marina Cavazzana, Frederic D Bushman
Integration of new DNA into cellular genomes mediates replication of retroviruses and transposons; integration reactions have also been adapted for use in human gene therapy. Tracking the distributions of integration sites is important to characterize populations of transduced cells and to monitor potential outgrow of pathogenic cell clones. Here, we describe a pipeline for quantitative analysis of integration site distributions named INSPIIRED (integration site pipeline for paired-end reads). We describe optimized biochemical steps for site isolation using Illumina paired-end sequencing, including new technology for suppressing recovery of unwanted contaminants, then software for alignment, quality control, and management of integration site sequences...
March 17, 2017: Molecular Therapy. Methods & Clinical Development
https://www.readbyqxmd.com/read/28344988/inspiired-quantification-and-visualization-tools-for-analyzing-integration-site-distributions
#7
Charles C Berry, Christopher Nobles, Emmanuelle Six, Yinghua Wu, Nirav Malani, Eric Sherman, Anatoly Dryga, John K Everett, Frances Male, Aubrey Bailey, Kyle Bittinger, Mary J Drake, Laure Caccavelli, Paul Bates, Salima Hacein-Bey-Abina, Marina Cavazzana, Frederic D Bushman
Analysis of sites of newly integrated DNA in cellular genomes is important to several fields, but methods for analyzing and visualizing these datasets are still under development. Here, we describe tools for data analysis and visualization that take as input integration site data from our INSPIIRED pipeline. Paired-end sequencing allows inference of the numbers of transduced cells as well as the distributions of integration sites in target genomes. We present interactive heatmaps that allow comparison of distributions of integration sites to genomic features and that support numerous user-defined statistical tests...
March 17, 2017: Molecular Therapy. Methods & Clinical Development
https://www.readbyqxmd.com/read/28344933/precision-medicine-the-golden-gate-for-detection-treatment-and-prevention-of-alzheimer-s-disease
#8
H Hampel, S E O'Bryant, J I Castrillo, C Ritchie, K Rojkova, K Broich, N Benda, R Nisticò, R A Frank, B Dubois, V Escott-Price, S Lista
During this decade, breakthrough conceptual shifts have commenced to emerge in the field of Alzheimer's disease (AD) recognizing risk factors and the non-linear dynamic continuum of complex pathophysiologies amongst a wide dimensional spectrum of multi-factorial brain proteinopathies/neurodegenerative diseases. As is the case in most fields of medicine, substantial advancements in detecting, treating and preventing AD will likely evolve from the generation and implementation of a systematic precision medicine strategy...
December 2016: Journal of Prevention of Alzheimer's Disease
https://www.readbyqxmd.com/read/28343068/the-role-of-trail-in-fatigue-induced-by-repeated-stress-from-radiotherapy
#9
Li Rebekah Feng, Simeng Suy, Sean P Collins, Leorey N Saligan
Fatigue is one of the most common and debilitating side effects of cancer and cancer treatment, and yet its etiology remains elusive. The goal of this study is to understand the role of chronic inflammation in fatigue following repeated stress from radiotherapy. Fatigue and non-fatigue categories were assessed using ≥ 3-point change in Functional Assessment of Cancer Therapy-Fatigue questionnaire (FACT-F) administered to participants at baseline/before radiotherapy and one year post-radiotherapy. Whole genome microarray and cytokine multiplex panel were used to examine fatigue-related transcriptome and serum cytokine changes, respectively...
March 20, 2017: Journal of Psychiatric Research
https://www.readbyqxmd.com/read/28342986/oncogenic-roles-of-dna-hypomethylation-through-the-activation-of-cancer-germline-genes
#10
Aurélie Van Tongelen, Axelle Loriot, Charles De Smet
Global loss of DNA methylation is frequently observed in the genome of human tumors. Although this epigenetic alteration is clearly associated with cancer progression, the way it exerts its pro-tumoral effect remains incompletely understood. A remarkable consequence of DNA hypomethylation in tumors is the aberrant activation of "cancer-germline" genes (also known as "cancer-testis" genes), which comprise a diverse group of germline-specific genes that use DNA methylation as a primary mechanism for repression in normal somatic tissues...
March 22, 2017: Cancer Letters
https://www.readbyqxmd.com/read/28340620/stable-high-level-expression-of-factor-viii-in-chinese-hamster-ovary-cells-in-improved-elongation-factor-1-alpha-based-system
#11
Nadezhda A Orlova, Sergey V Kovnir, Alexandre G Gabibov, Ivan I Vorobiev
BACKGROUND: Recombinant factor VIII (FVIII), used for haemophilia A therapy, is one of the most challenging among the therapeutic proteins produced in heterologous expression systems. Deletion variant of FVIII, in which the entire domain B is replaced by a short linker peptide, was approved for medical use. Efficacy and safety of this FVIII deletion variant are similar to full-length FVIII preparations while the level of production in CHO cells is substantially higher. Typical levels of productivity for CHO cell lines producing deletion variant FVIII-BDD SQ, described elsewhere, are 0...
March 24, 2017: BMC Biotechnology
https://www.readbyqxmd.com/read/28339881/genetic-aspects-and-environmental-sources-of-microsporidia-that-infect-the-human-gastrointestinal-tract
#12
Martin F Heyworth
Enterocytozoon bieneusi and Encephalitozoon intestinalis are microsporidia that infect the human gastrointestinal (GI) tract. Each of these microsporidia has been shown to infect various non-human hosts (mammalian and avian), raising the possibility of inter-species transmission, for example, from such hosts to human subjects via waterborne dispersal of microsporidian spores. During the past two decades, genome sequencing has delineated more than 90 genotypes of Ent. bieneusi, and has led to the conclusion that not all the genotypes of this organism infect human subjects...
February 27, 2017: Transactions of the Royal Society of Tropical Medicine and Hygiene
https://www.readbyqxmd.com/read/28339517/omics-studies-their-use-in-diagnosis-and-reclassification-of-sle-and-other-systemic-autoimmune-diseases
#13
Maria Teruel, Chris Chamberlain, Marta E Alarcón-Riquelme
Omics studies of systemic autoimmune diseases (SADs) in general, and SLE in particular, have delivered isolated information from transcriptome, epigenome, genome, cytokine and metabolome analyses. Such analyses have resulted in the identification of disease susceptibility genes and the description of IFN expression signatures, allowing extensive insight into the mechanisms of disease and the development of new therapies. Access to such technologies allows the recognition of patterns of disease at a pathway level, thereby, to reclassify SLE and other SADs and to develop new therapeutics from a personalized perspective...
October 19, 2016: Rheumatology
https://www.readbyqxmd.com/read/28339063/viral-and-host-factors-associated-with-outcomes-of-hepatitis-c-virus-infection-review
#14
Zehui Yan, Yuming Wang
Hepatitis C virus (HCV) infection is a major health issue globally. Owing to the progress made in host genetics and HCV molecular virology, emerging data have suggested that the natural course and treatment response in patients with HCV infection are largely determined by complex host‑viral interactions. HCV genotype is the most important viral factor predicting the response to pegylated interferon‑α plus ribavirin therapy. The subtype of HCV genotype 1 is the key viral factor that predicts the efficacy of direct‑acting antiviral therapy...
March 22, 2017: Molecular Medicine Reports
https://www.readbyqxmd.com/read/28338660/germline-and-somatic-genetics-of-osteosarcoma-connecting-aetiology-biology-and-therapy
#15
REVIEW
D Matthew Gianferante, Lisa Mirabello, Sharon A Savage
Clinical outcomes and treatment modalities for osteosarcoma, the most common primary cancer of bone, have changed very little over the past 30 years. The peak incidence of osteosarcoma occurs during the adolescent growth spurt, which suggests that bone growth and pubertal hormones are important in the aetiology of the disease. Tall stature, high birth weight and certain inherited cancer predisposition syndromes are well-described risk factors for osteosarcoma. Common genetic variants are also associated with osteosarcoma...
March 24, 2017: Nature Reviews. Endocrinology
https://www.readbyqxmd.com/read/28338654/tfeb-vegfa-6p21-1-co-amplified-renal-cell-carcinoma-a-distinct-entity-with-potential-implications-for-clinical-management
#16
Sounak Gupta, Sarah H Johnson, George Vasmatzis, Binu Porath, Jeannette G Rustin, Priya Rao, Brian A Costello, Bradley C Leibovich, R Houston Thompson, John C Cheville, William R Sukov
A subset of renal cell carcinomas shows TFEB overexpression secondary to MALAT1-TFEB gene fusion. As alternate mechanisms of TFEB overexpression are likely to have the same effect, we sought to determine the frequency of amplification of TFEB and the adjacent VEGFA gene at 6p21.1. As patients with metastatic renal cell carcinomas are managed with anti-VEGF therapies, we retrospectively assessed therapeutic response in patients with amplified tumors. Amplification status was analyzed for 875 renal cell carcinomas from our institution, a consultative case and 794 cases from The Cancer Genome Atlas...
March 24, 2017: Modern Pathology: An Official Journal of the United States and Canadian Academy of Pathology, Inc
https://www.readbyqxmd.com/read/28337020/delivery-technologies-for-genome-editing
#17
REVIEW
Hao Yin, Kevin J Kauffman, Daniel G Anderson
With the recent development of CRISPR technology, it is becoming increasingly easy to engineer the genome. Genome-editing systems based on CRISPR, as well as transcription activator-like effector nucleases (TALENs) and zinc-finger nucleases (ZFNs), are becoming valuable tools for biomedical research, drug discovery and development, and even gene therapy. However, for each of these systems to effectively enter cells of interest and perform their function, efficient and safe delivery technologies are needed. This Review discusses the principles of biomacromolecule delivery and gene editing, examines recent advances and challenges in non-viral and viral delivery methods, and highlights the status of related clinical trials...
March 24, 2017: Nature Reviews. Drug Discovery
https://www.readbyqxmd.com/read/28336253/mitochondrial-matters-mitochondrial-bottlenecks-self-assembling-structures-and-entrapment-in-the-female-germline
#18
Florence L Marlow
Mitochondrial replacement therapy, a procedure to generate embryos with the nuclear genome of a donor mother and the healthy mitochondria of a recipient egg, has recently emerged as a promising strategy to prevent transmission of devastating mitochondrial DNA diseases and infertility. The procedure may produce an embryo that is free of diseased mitochondria. A recent study addresses important fundamental questions about the mechanisms underlying maternal inheritance and translational questions regarding the transgenerational effectiveness of this promising therapeutic strategy...
March 15, 2017: Stem Cell Research
https://www.readbyqxmd.com/read/28335547/genomic-loads-and-genotypes-of-respiratory-syncytial-virus-viral-factors-during-lower-respiratory-tract-infection-in-chilean-hospitalized-infants
#19
Yazmín Espinosa, Camila San Martín, Alejandro A Torres, Mauricio J Farfán, Juan P Torres, Vasanthi Avadhanula, Pedro A Piedra, Lorena I Tapia
The clinical impact of viral factors (types and viral loads) during respiratory syncytial virus (RSV) infection is still controversial, especially regarding newly described genotypes. In this study, infants with RSV bronchiolitis were recruited to describe the association of these viral factors with severity of infection. RSV antigenic types, genotypes, and viral loads were determined from hospitalized patients at Hospital Roberto del Río, Santiago, Chile. Cases were characterized by demographic and clinical information, including days of lower respiratory symptoms and severity...
March 21, 2017: International Journal of Molecular Sciences
https://www.readbyqxmd.com/read/28335410/non-canonical-roles-of-dengue-virus-non-structural-proteins
#20
REVIEW
Julianna D Zeidler, Lorena O Fernandes-Siqueira, Glauce M Barbosa, Andrea T Da Poian
The Flaviviridae family comprises a number of human pathogens, which, although sharing structural and functional features, cause diseases with very different outcomes. This can be explained by the plurality of functions exerted by the few proteins coded by viral genomes, with some of these functions shared among members of a same family, but others being unique for each virus species. These non-canonical functions probably have evolved independently and may serve as the base to the development of specific therapies for each of those diseases...
March 13, 2017: Viruses
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