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Mutational robustness

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https://www.readbyqxmd.com/read/28427233/assessment-of-the-interlaboratory-variability-and-robustness-of-jak2v617f-mutation-assays-a-study-involving-a-consortium-of-19-italian-laboratories
#1
Margherita Perricone, Francesca Palandri, Emanuela Ottaviani, Mario Angelini, Laura Bagli, Enrica Bellesia, Meris Donati, Donato Gemmati, Patrizia Zucchini, Stefania Mancini, Valentina Marchica, Serena Trubini, Giovanna De Matteis, Silvia Di Zacomo, Mosè Favarato, Annamaria Fioroni, Caterina Bolzonella, Giorgia Maccari, Filippo Navaglia, Daniela Gatti, Luisa Toffolatti, Linda Orlandi, Vèronique Laloux, Marco Manfrini, Piero Galieni, Barbara Giannini, Alessia Tieghi, Sara Barulli, Maria Luisa Serino, Monica Maccaferri, Anna Rita Scortechini, Nicola Giuliani, Daniele Vallisa, Massimiliano Bonifacio, Patrizia Accorsi, Cristina Salbe, Vinicio Fazio, Milena Gusella, Eleonora Toffoletti, Marzia Salvucci, Mirija Svaldi, Filippo Gherlinzoni, Francesca Cassavia, Francesco Orsini, Giovanni Martinelli
To date, a plenty of techniques for the detection of JAK2V617F is used over different laboratories, with substantial differences in specificity and sensitivity. Therefore, to provide reliable and comparable results, the standardization of molecular techniques is mandatory.A network of 19 centers was established to 1) evaluate the inter- and intra-laboratory variability in JAK2V617F quantification, 2) identify the most robust assay for the standardization of the molecular test and 3) allow consistent interpretation of individual patient analysis results...
March 6, 2017: Oncotarget
https://www.readbyqxmd.com/read/28424288/virion-associated-vpr-alleviates-a-post-integration-block-to-hiv-1-infection-of-dendritic-cells
#2
Caitlin M Miller, Hisashi Akiyama, Luis M Agosto, Ann Emery, Chelsea R Ettinger, Ronald I Swamstrom, Andrew J Henderson, Suryaram Gummuluru
Viral protein R (Vpr) is an HIV-1 accessory protein whose function remains poorly understood. In this report, we sought to determine the requirement of Vpr in facilitating HIV-1 infection of monocyte-derived dendritic cells (MDDCs), one of the first cells to encounter virus in the peripheral mucosal tissues. We characterize in this report a significant restriction to Vpr-deficient virus replication and spread in MDDCs alone and in cell-to-cell spread in MDDC - CD4(+) T cell co-cultures. This restriction to HIV-1 replication in MDDCs was observed in a single round of virus replication and was rescued by expression of Vpr in trans in the incoming virion...
April 19, 2017: Journal of Virology
https://www.readbyqxmd.com/read/28423717/non-homologous-end-joining-induced-alterations-in-dna-methylation-a-source-of-permanent-epigenetic-change
#3
Brittany Allen, Antonio Pezone, Antonio Porcellini, Mark T Muller, Michal M Masternak
In addition to genetic mutations, epigenetic revision plays a major role in the development and progression of cancer; specifically, inappropriate DNA methylation or demethylation of CpG residues may alter the expression of genes that promote tumorigenesis. We hypothesize that DNA repair, specifically the repair of DNA double strand breaks (DSB) by Non-Homologous End Joining (NHEJ) may play a role in this process. Using a GFP reporter system inserted into the genome of HeLa cells, we are able to induce targeted DNA damage that enables the cells, after successfully undergoing NHEJ repair, to express WT GFP...
March 11, 2017: Oncotarget
https://www.readbyqxmd.com/read/28423702/experience-with-precision-genomics-and-tumor-board-indicates-frequent-target-identification-but-barriers-to-delivery
#4
Alan H Bryce, Jan B Egan, Mitesh J Borad, A Keith Stewart, Grzegorz S Nowakowski, Asher Chanan-Khan, Mrinal M Patnaik, Stephen M Ansell, Michaela S Banck, Steven I Robinson, Aaron S Mansfield, Eric W Klee, Gavin R Oliver, Jennifer B McCormick, Norine E Huneke, Colleen M Tagtow, Robert B Jenkins, Kandelaria M Rumilla, Sarah E Kerr, Jean-Pierre A Kocher, Scott A Beck, Martin E Fernandez-Zapico, Gianrico Farrugia, Konstantinos N Lazaridis, Robert R McWilliams
BACKGROUND: The ability to analyze the genomics of malignancies has opened up new possibilities for off-label targeted therapy in cancers that are refractory to standard therapy. At Mayo Clinic these efforts are organized through the Center for Individualized Medicine (CIM). RESULTS: Prior to GTB, datasets were analyzed and integrated by a team of bioinformaticians and cancer biologists. Therapeutically actionable mutations were identified in 65% (92/141) of the patients tested with 32% (29/92) receiving genomically targeted therapy with FDA approved drugs or in an independent clinical trial with 45% (13/29) responding...
March 9, 2017: Oncotarget
https://www.readbyqxmd.com/read/28422714/toll-like-receptor-3-as-an-immunotherapeutic-target-for-kras-mutated-colorectal-cancer
#5
Radhashree Maitra, Titto Augustine, Yitzchak Dayan, Carol Chandy, Matthew Coffey, Sanjay Goel
New therapeutic interventions are essential for improved management of patients with metastatic colorectal cancer (mCRC). This is especially critical for those patients whose tumors harbor a mutation in the KRAS oncogene (40-45% of all patients). This patient cohort is excluded from receiving anti-EGFR monoclonal antibodies that have added a significant therapeutic benefit for KRAS wild type CRC patients. Reovirus, a double stranded (ds) RNA virus is in clinical development for patients with chemotherapy refractory KRAS mutated tumors...
April 4, 2017: Oncotarget
https://www.readbyqxmd.com/read/28420412/intersect-then-combine-approach-improving-the-performance-of-somatic-variant-calling-in-whole-exome-sequencing-data-using-multiple-aligners-and-callers
#6
Maurizio Callari, Stephen-John Sammut, Leticia De Mattos-Arruda, Alejandra Bruna, Oscar M Rueda, Suet-Feung Chin, Carlos Caldas
Bioinformatic analysis of genomic sequencing data to identify somatic mutations in cancer samples is far from achieving the required robustness and standardisation. In this study we generated a whole exome sequencing benchmark dataset using the platinum genome sample NA12878 and developed an intersect-then-combine (ITC) approach to increase the accuracy in calling single nucleotide variants (SNVs) and indels in tumour-normal pairs. We evaluated the effect of alignment, base quality recalibration, mutation caller and filtering on sensitivity and false positive rate...
April 18, 2017: Genome Medicine
https://www.readbyqxmd.com/read/28416701/defective-synaptic-connectivity-and-axonal-neuropathology-in-a-human-ipsc-based-model-of-familial-parkinson-s-disease
#7
Georgia Kouroupi, Era Taoufik, Ioannis S Vlachos, Konstantinos Tsioras, Nasia Antoniou, Florentia Papastefanaki, Dafni Chroni-Tzartou, Wolfgang Wrasidlo, Delphine Bohl, Dimitris Stellas, Panagiotis K Politis, Kostas Vekrellis, Dimitra Papadimitriou, Leonidas Stefanis, Piotr Bregestovski, Artemis G Hatzigeorgiou, Eliezer Masliah, Rebecca Matsas
α-Synuclein (αSyn) is the major gene linked to sporadic Parkinson's disease (PD), whereas the G209A (p.A53T) αSyn mutation causes a familial form of PD characterized by early onset and a generally severe phenotype, including nonmotor manifestations. Here we generated de novo induced pluripotent stem cells (iPSCs) from patients harboring the p.A53T mutation and developed a robust model that captures PD pathogenic processes under basal conditions. iPSC-derived mutant neurons displayed novel disease-relevant phenotypes, including protein aggregation, compromised neuritic outgrowth, and contorted or fragmented axons with swollen varicosities containing αSyn and Tau...
April 17, 2017: Proceedings of the National Academy of Sciences of the United States of America
https://www.readbyqxmd.com/read/28415721/robust-in-silico-identification-of-cancer-cell-lines-based-on-next-generation-sequencing
#8
Raik Otto, Christine Sers, Ulf Leser
Cancer cell lines (CCL) are important tools for cancer researchers world-wide. However, handling of cancer cell lines is error-prone, and critical errors such as misidentification and cross-contamination occur more often than acceptable. Based on the fact that CCL today very often are sequenced (partly or entirely) anyway as part of the studies performed, we developed Uniquorn, a computational method that reliably identifies CCL samples based on variant profiles derived from whole exome or whole genome sequencing...
March 10, 2017: Oncotarget
https://www.readbyqxmd.com/read/28414320/inhibition-of-dna2-nuclease-as-a-therapeutic-strategy-targeting-replication-stress-in-cancer-cells
#9
S Kumar, X Peng, J Daley, L Yang, J Shen, N Nguyen, G Bae, H Niu, Y Peng, H-J Hsieh, L Wang, C Rao, C C Stephan, P Sung, G Ira, G Peng
Replication stress is a characteristic feature of cancer cells, which is resulted from sustained proliferative signaling induced by activation of oncogenes or loss of tumor suppressors. In cancer cells, oncogene-induced replication stress manifests as replication-associated lesions, predominantly double-strand DNA breaks (DSBs). An essential mechanism utilized by cells to repair replication-associated DSBs is homologous recombination (HR). In order to overcome replication stress and survive, cancer cells often require enhanced HR repair capacity...
April 17, 2017: Oncogenesis
https://www.readbyqxmd.com/read/28413720/direct-imaging-of-app-proteolysis-in-living-cells
#10
Niccoló Parenti, Ambra Del Grosso, Claudia Antoni, Marco Cecchini, Renato Corradetti, Francesco S Pavone, Martino Calamai
Alzheimer's disease is a multifactorial disorder caused by the interaction of genetic, epigenetic and environmental factors. The formation of cytotoxic oligomers consisting of Aβ peptide is widely accepted as being one of the main key events triggering the development of Alzheimer's disease. Aβ peptide production results from the specific proteolytic processing of the amyloid precursor protein (APP). Deciphering the factors governing the activity of the secretases responsible for the cleavage of APP is still a critical issue...
2017: PeerJ
https://www.readbyqxmd.com/read/28413162/whole-genome-sequence-of-the-metastatic-pc3-and-lncap-human-prostate-cancer-cell-lines
#11
Inge Seim, Penny L Jeffery, Patrick B Thomas, Colleen C Nelson, Lisa K Chopin
The bone metastasis-derived PC3 and the lymph node metastasis-derived LNCaP prostate cancer cell lines are widely studied, having been described in thousands of publications over the last four decades. Here, we report short-read whole-genome sequencing and de novo assembly of PC3 (ATCC CRL-1435) and LNCaP (clone FGC; ATCC CRL-1740) at ~70X coverage. A known homozygous mutation in TP53 and homozygous loss of PTEN were robustly identified in the PC3 cell line, whereas the LNCaP cell line exhibited a larger number of putative inactivating somatic point and indel mutations (and in particular loss of stop codon events)...
April 16, 2017: G3: Genes—Genomes—Genetics
https://www.readbyqxmd.com/read/28408900/the-thrombopoietin-receptor-structural-basis-of-traffic-and-activation-by-ligand-mutations-agonists-and-mutated-calreticulin
#12
REVIEW
Leila N Varghese, Jean-Philippe Defour, Christian Pecquet, Stefan N Constantinescu
A well-functioning hematopoietic system requires a certain robustness and flexibility to maintain appropriate quantities of functional mature blood cells, such as red blood cells and platelets. This review focuses on the cytokine receptor that plays a significant role in thrombopoiesis: the receptor for thrombopoietin (TPO-R; also known as MPL). Here, we survey the work to date to understand how this receptor functions at a molecular level throughout its lifecycle, from traffic to the cell surface, dimerization and binding cognate cytokine via its extracellular domain, through to its subsequent activation of associated Janus kinases and initiation of downstream signaling pathways, as well as the regulation of these processes...
2017: Frontiers in Endocrinology
https://www.readbyqxmd.com/read/28407998/a-cost-effectiveness-evaluation-of-germline-brca1-and-brca2-testing-in-uk-women-with-ovarian-cancer
#13
Anthony Eccleston, Anthony Bentley, Matthew Dyer, Ann Strydom, Wim Vereecken, Angela George, Nazneen Rahman
OBJECTIVES: To evaluate the long-term cost-effectiveness of germline BRCA1 and BRCA2 (collectively termed "BRCA") testing in women with epithelial ovarian cancer, and testing for the relevant mutation in first- and second-degree relatives of BRCA mutation-positive individuals, compared with no testing. Female BRCA mutation-positive relatives of patients with ovarian cancer could undergo risk-reducing mastectomy and/or bilateral salpingo-oophorectomy. METHODS: A cost-effectiveness model was developed that included the risks of breast and ovarian cancer; the costs, utilities, and effects of risk-reducing surgery on cancer rates; and the costs, utilities, and mortality rates associated with cancer...
April 2017: Value in Health: the Journal of the International Society for Pharmacoeconomics and Outcomes Research
https://www.readbyqxmd.com/read/28407867/the-relationship-between-mitochondrial-dna-copy-number-and-stallion-sperm-function
#14
Christa R Darr, Luis E Moraes, Richard E Connon, Charles C Love, Sheila Teague, Dickson D Varner, Stuart A Meyers
Mitochondrial DNA (mtDNA) copy number has been utilized as a measure of sperm quality in several species including mice, dogs, and humans, and has been suggested as a potential biomarker of fertility in stallion sperm. The results of the present study extend this recent discovery using sperm samples from American Quarter Horse stallions of varying age. By determining copy number of three mitochondrial genes, cytochrome b (CYTB), NADH dehydrogenase 1 (ND1) and NADH dehydrogenase 4 (ND4), instead of a single gene, we demonstrate an improved understanding of mtDNA fate in stallion sperm mitochondria following spermatogenesis...
May 2017: Theriogenology
https://www.readbyqxmd.com/read/28407804/mathematical-model-of-tgf-%C3%AE-signalling-feedback-coupling-is-consistent-with-signal-switching
#15
Shabnam Khatibi, Hong-Jian Zhu, John Wagner, Chin Wee Tan, Jonathan H Manton, Antony W Burgess
BACKGROUND: Transforming growth factor β (TGF-β) signalling regulates the development of embryos and tissue homeostasis in adults. In conjunction with other oncogenic changes, long-term perturbation of TGF-β signalling is associated with cancer metastasis. Although TGF-β signalling can be complex, many of the signalling components are well defined, so it is possible to develop mathematical models of TGF-β signalling using reduction and scaling methods. The parameterization of our TGF-β signalling model is consistent with experimental data...
April 13, 2017: BMC Systems Biology
https://www.readbyqxmd.com/read/28407791/accelerated-differentiation-of-human-induced-pluripotent-stem-cells-to-blood-brain-barrier-endothelial-cells
#16
Emma K Hollmann, Amanda K Bailey, Archit V Potharazu, M Diana Neely, Aaron B Bowman, Ethan S Lippmann
BACKGROUND: Due to their ability to limitlessly proliferate and specialize into almost any cell type, human induced pluripotent stem cells (iPSCs) offer an unprecedented opportunity to generate human brain microvascular endothelial cells (BMECs), which compose the blood-brain barrier (BBB), for research purposes. Unfortunately, the time, expense, and expertise required to differentiate iPSCs to purified BMECs precludes their widespread use. Here, we report the use of a defined medium that accelerates the differentiation of iPSCs to BMECs while achieving comparable performance to BMECs produced by established methods...
April 13, 2017: Fluids and Barriers of the CNS
https://www.readbyqxmd.com/read/28407294/altered-tert-promoter-and-other-genomic-regulatory-elements-occurrence-and-impact
#17
Barbara Heidenreich, Rajiv Kumar
Study of genetic alterations, inherited or acquired, that increase the risk or drive cancers and many other diseases had remained mostly confined to coding sequences of the human genome. Data from genome wide associations studies, development of the Encyclopedia of DNA Elements (ENCODE), and a spurt in detection of driver somatic mutations have shifted focus towards noncoding regions of the human genome. The majority of genetic variants robustly associated with cancers and other syndromes identified through genome wide studies are located within noncoding regulatory regions of the genome...
April 13, 2017: International Journal of Cancer. Journal International du Cancer
https://www.readbyqxmd.com/read/28404952/high-throughput-detection-of-clinically-targetable-alterations-using-next-generation-sequencing
#18
Julie A Vendrell, David Grand, Isabelle Rouquette, Valérie Costes, Samira Icher, Janick Selves, Marion Larrieux, Aurore Barbe, Pierre Brousset, Jérôme Solassol
Next-generation sequencing (NGS) has revolutionized the therapeutic care of patients by allowing high-throughput and parallel sequencing of large numbers of genes in a single run. However, most of available commercialized cancer panels target a large number of mutations that do not have direct therapeutic implications and that are not fully adapted to low quality formalin-fixed, paraffin-embedded (FFPE) samples. Here, we designed an amplicon-based NGS panel assay of 16 currently actionable genes according to the most recent recommendations of the French National Cancer Institute (NCI)...
March 3, 2017: Oncotarget
https://www.readbyqxmd.com/read/28402852/an-activating-stat3-mutation-causes-neonatal-diabetes-through-premature-induction-of-pancreatic-differentiation
#19
Jonna Saarimäki-Vire, Diego Balboa, Mark A Russell, Juha Saarikettu, Matias Kinnunen, Salla Keskitalo, Amrinder Malhi, Cristina Valensisi, Colin Andrus, Solja Eurola, Heli Grym, Jarkko Ustinov, Kirmo Wartiovaara, R David Hawkins, Olli Silvennoinen, Markku Varjosalo, Noel G Morgan, Timo Otonkoski
Activating germline mutations in STAT3 were recently identified as a cause of neonatal diabetes mellitus associated with beta-cell autoimmunity. We have investigated the effect of an activating mutation, STAT3(K392R), on pancreatic development using induced pluripotent stem cells (iPSCs) derived from a patient with neonatal diabetes and pancreatic hypoplasia. Early pancreatic endoderm differentiated similarly from STAT3(K392R) and healthy-control cells, but in later stages, NEUROG3 expression was upregulated prematurely in STAT3(K392R) cells together with insulin (INS) and glucagon (GCG)...
April 11, 2017: Cell Reports
https://www.readbyqxmd.com/read/28400513/determining-the-factors-driving-selective-effects-of-new-nonsynonymous-mutations
#20
Christian D Huber, Bernard Y Kim, Clare D Marsden, Kirk E Lohmueller
The distribution of fitness effects (DFE) of new mutations plays a fundamental role in evolutionary genetics. However, the extent to which the DFE differs across species has yet to be systematically investigated. Furthermore, the biological mechanisms determining the DFE in natural populations remain unclear. Here, we show that theoretical models emphasizing different biological factors at determining the DFE, such as protein stability, back-mutations, species complexity, and mutational robustness make distinct predictions about how the DFE will differ between species...
April 11, 2017: Proceedings of the National Academy of Sciences of the United States of America
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