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https://www.readbyqxmd.com/read/28806273/the-changing-landscape-of-gene-editing-in-hematopoietic-stem-cells-a-step-towards-cas9-clinical-translation
#1
Daniel P Dever, Matthew H Porteus
PURPOSE OF REVIEW: Since the discovery two decades ago that programmable endonucleases can be engineered to modify human cells at single nucleotide resolution, the concept of genome editing was born. Now these technologies are being applied to therapeutically relevant cell types, including hematopoietic stem cells (HSC), which possess the power to repopulate an entire blood and immune system. The purpose of this review is to discuss the changing landscape of genome editing in hematopoietic stem cells (GE-HSC) from the discovery stage to the preclinical stage, with the imminent goal of clinical translation for the treatment of serious genetic diseases of the blood and immune system...
August 12, 2017: Current Opinion in Hematology
https://www.readbyqxmd.com/read/28805815/aav-mediated-direct-in-vivo-crispr-screen-identifies-functional-suppressors-in-glioblastoma
#2
Ryan D Chow, Christopher D Guzman, Guangchuan Wang, Florian Schmidt, Mark W Youngblood, Lupeng Ye, Youssef Errami, Matthew B Dong, Michael A Martinez, Sensen Zhang, Paul Renauer, Kaya Bilguvar, Murat Gunel, Phillip A Sharp, Feng Zhang, Randall J Platt, Sidi Chen
A causative understanding of genetic factors that regulate glioblastoma pathogenesis is of central importance. Here we developed an adeno-associated virus-mediated, autochthonous genetic CRISPR screen in glioblastoma. Stereotaxic delivery of a virus library targeting genes commonly mutated in human cancers into the brains of conditional-Cas9 mice resulted in tumors that recapitulate human glioblastoma. Capture sequencing revealed diverse mutational profiles across tumors. The mutation frequencies in mice correlated with those in two independent patient cohorts...
August 14, 2017: Nature Neuroscience
https://www.readbyqxmd.com/read/28802906/pathways-towards-indolent-b-cell-lymphoma-etiology-and-therapeutic-strategies
#3
REVIEW
Michiel van den Brand, Blanca Scheijen, Corine J Hess, J Han Jm van Krieken, Patricia J T A Groenen
Although patients with indolent B-cell lymphomas have a relatively good survival rate, conventional chemotherapy is not curative. Disease courses are typically characterized by multiple relapses and progressively shorter response duration with subsequent lines of therapy. There has been an explosion of innovative targeted agents in the past years. This review discusses current knowledge on the etiology of indolent B-cell lymphomas with respect to the role of micro-organisms, auto-immune diseases, and deregulated pathways caused by mutations...
August 5, 2017: Blood Reviews
https://www.readbyqxmd.com/read/28802078/geographical-features-are-the-predominant-driver-of-molecular-diversification-in-widely-distributed-north-american-whipsnakes
#4
Kyle A O'Connell, Jeffrey W Streicher, Eric N Smith, Matthew K Fujita
Allopatric divergence following the formation of geographical features has been implicated as a major driver of evolutionary diversification. Widespread species complexes provide opportunities to examine allopatric divergence across varying degrees of isolation in both time and space. In North America, several geographical features may play such a role in diversification, including the Mississippi River, Pecos River, Rocky Mountains, Cochise Filter Barrier, Gulf of California, and Isthmus of Tehuantepec. We used thousands of nuclear single nucleotide polymorphisms (SNPs) and mitochondrial DNA from several species of whipsnakes (genera Masticophis and Coluber) distributed across North and Central America to investigate the role that these geographical features have played on lineage divergence...
August 12, 2017: Molecular Ecology
https://www.readbyqxmd.com/read/28796434/a-comparison-of-regression-methods-for-model-selection-in-individual-based-landscape-genetic-analysis
#5
A J Shirk, E L Landguth, S A Cushman
Anthropogenic migration barriers fragment many populations and limit the ability of species to respond to climate-induced biome shifts. Conservation actions designed to conserve habitat connectivity and mitigate barriers are needed to unite fragmented populations into larger, more viable metapopulations, and to allow species to track their climate envelope over time. Landscape genetic analysis provides an empirical means to infer landscape factors influencing gene flow, and thereby inform such conservation actions...
August 10, 2017: Molecular Ecology Resources
https://www.readbyqxmd.com/read/28790435/emergence-of-a-streptococcus-dysgalactiae-subspecies-equisimilis-stg62647-lineage-associated-with-severe-clinical-manifestations
#6
Oddvar Oppegaard, Haima Mylvaganam, Steinar Skrede, Paul Christoffer Lindemann, Bård Reiakvam Kittang
Increasing incidence rates of invasive Streptococcus dysgalactiae subspecies equisimilis (SDSE) infections have been reported worldwide, but the evolutionary mechanisms underlying this development remain elusive. Through prospective surveillance of invasive SDSE infections in western Norway, we observed the emergence of a novel and virulent SDSE genotype, stG62647. This emm-type, rarely encountered as a cause of invasive disease during 1999-2012, emerged in 2013 as the predominant SDSE-genotype. The stG62647-infections were associated with an aggressive clinical course, including the occurrence of streptococcal toxic shock syndrome, necrotizing soft-tissue infections and endocarditis...
August 8, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28790313/evolution-of-new-regulatory-functions-on-biophysically-realistic-fitness-landscapes
#7
Tamar Friedlander, Roshan Prizak, Nicholas H Barton, Gašper Tkačik
Gene expression is controlled by networks of regulatory proteins that interact specifically with external signals and DNA regulatory sequences. These interactions force the network components to co-evolve so as to continually maintain function. Yet, existing models of evolution mostly focus on isolated genetic elements. In contrast, we study the essential process by which regulatory networks grow: the duplication and subsequent specialization of network components. We synthesize a biophysical model of molecular interactions with the evolutionary framework to find the conditions and pathways by which new regulatory functions emerge...
August 9, 2017: Nature Communications
https://www.readbyqxmd.com/read/28790112/burden-and-profile-of-somatic-mutation-in-duodenal-adenomas-from-patients-with-familial-adenomatous-and-mutyh-associated-polyposis
#8
Laura Elizabeth Thomas, Joanna J Hurley, Elena Meuser, Sian Jose, Kevin E Ashelford, Matthew Mort, Shelley Idziaszczyk, Julie Maynard, Helena Leon Brito, Manon Harry, Angharad Walters, Meera Raja, Sarah Jane Walton, Sunil Dolwani, Geraint T Williams, Meleri Morgan, Morgan Moorghen, Susan K Clark, Julian R Sampson
Duodenal polyposis and cancer are important causes of morbidity and mortality in familial adenomatous polyposis (FAP) and MUTYH-associated polyposis (MAP). This study aimed to comprehensively characterize somatic genetic changes in FAP and MAP duodenal adenomas to better understand duodenal tumorigenesis in these disorders.<br /><br />Experimental Design: Sixty-nine adenomas were biopsied during endoscopy in 16 FAP and 10 MAP patients with duodenal polyposis. Ten FAP and 10 MAP adenomas and matched blood DNA samples were exome sequenced, 42 further adenomas underwent targeted sequencing and 47 were studied by array comparative genomic hybridization...
August 8, 2017: Clinical Cancer Research: An Official Journal of the American Association for Cancer Research
https://www.readbyqxmd.com/read/28782804/discovery-of-long-distance-gamete-dispersal-in-a-lichen-forming-ascomycete
#9
Cecilia Ronnås, Silke Werth, Otso Ovaskainen, Gergely Várkonyi, Christoph Scheidegger, Tord Snäll
Accurate estimates of gamete and offspring dispersal range are required for the understanding and prediction of spatial population dynamics and species persistence. Little is known about gamete dispersal in fungi, especially in lichen-forming ascomycetes. Here, we estimate the dispersal functions of clonal propagules, gametes and ascospores of the epiphytic lichen Lobaria pulmonaria. We use hierarchical Bayesian parentage analysis, which integrates genetic and ecological information from multiannual colonization and dispersal source data collected in a large, old-growth forest landscape...
August 7, 2017: New Phytologist
https://www.readbyqxmd.com/read/28782482/drug-combination-in-clinical-cancer-treatments
#10
Da-Yong Lu, Ting-Ren Lu, Nagendra Sastry Yarla, Hong-Ying Wu, Bin Xu, Jian Ding, Hong Zhu
AIM: The modality of anticancer drug combinations needs to be renovated from empirical into technical-supportive systems. METHODS: To challenge past therapeutic routines, the new landscape may be established. Among the different areas of anticancer drug combination study, research in the fields of medical study is the most important one-including disciplinary of therapeutics in different cancer stages, modern genetic/molecular diagnostics, cancer bioinformatics, traditional Chinese medicine, mathematical data analysis, therapeutic toxicity monitor, personalized cancer medicine and so on...
August 3, 2017: Reviews on Recent Clinical Trials
https://www.readbyqxmd.com/read/28777308/key-challenges-in-the-search-for-innovative-drug-treatments-for-special-populations-converging-needs-in-neonatology-pediatrics-and-medical-genetics
#11
Stuart MacLeod
The explosion of knowledge concerning the interplay of genetic and environmental factors determining pathophysiology and guiding therapeutic choice has altered the landscape in pediatric clinical pharmacology and pharmacy. The need for innovative research methods and design expertise for small clinical trials to be undertaken in sparse populations has been accentuated. At the same time, shortfalls in critical human resources represent a key challenge, especially in low- and middle-income countries where the need for new research and education directions is greatest...
August 4, 2017: Children
https://www.readbyqxmd.com/read/28776688/mosaics-often-outperform-pyramids-insights-from-a-model-comparing-strategies-for-the-deployment-of-plant-resistance-genes-against-viruses-in-agricultural-landscapes
#12
Ramses Djidjou-Demasse, Benoît Moury, Frédéric Fabre
The breakdown of plant virus resistance genes is a major issue in agriculture. We investigated whether a set of resistance genes would last longer when stacked into a single plant cultivar (pyramiding) or when deployed individually in regional mosaics (mosaic strategy). We modeled the genetic and epidemiological processes shaping the demogenetic dynamics of viruses under a multilocus gene-for-gene system, from the plant to landscape scales. The landscape consisted of many fields, was subject to seasonality, and of a reservoir hosting viruses year-round...
August 4, 2017: New Phytologist
https://www.readbyqxmd.com/read/28776571/expanded-molecular-profiling-of-myxofibrosarcoma-reveals-potentially-actionable-targets
#13
Ellen Heitzer, Sandra Sunitsch, Magdalena M Gilg, Birgit Lohberger, Beate Rinner, Karl Kashofer, Nicole Stündl, Peter Ulz, Joanna Szkandera, Andreas Leithner, Bernadette Liegl-Atzwanger
Myxofibrosarcomas are morphologically heterogeneous soft tissue sarcomas lacking a specific immunohistochemical expression profile and recurrent genetic changes. The study was designed to gain further insights into the molecular landscape of myxofibrosarcomas by targeted re-sequencing of known cancer driver hotspot mutations and the analysis of genomewide somatic copy number alterations. A well-defined group of myxofibrosarcomas, including myxofibrosarcomas G1 (n=6), myxofibrosarcomas G3 (n=7), myxofibrosarcomas with morphologically heterogeneous and independently selectable G1 and G3 areas within a tumor (n=8), and myxofibrosarcomas G3 with subsequent tumor recurrence (n=1) or metastatic disease (n=3) were evaluated...
August 4, 2017: Modern Pathology: An Official Journal of the United States and Canadian Academy of Pathology, Inc
https://www.readbyqxmd.com/read/28771629/altitudinal-gradients-biogeographic-history-and-microhabitat-adaptation-affect-fine-scale-spatial-genetic-structure-in-african-and-neotropical-populations-of-an-ancient-tropical-tree-species
#14
Paloma Torroba-Balmori, Katharina B Budde, Katrin Heer, Santiago C González-Martínez, Sanna Olsson, Caroline Scotti-Saintagne, Maxime Casalis, Bonaventure Sonké, Christopher W Dick, Myriam Heuertz
The analysis of fine-scale spatial genetic structure (FSGS) within populations can provide insights into eco-evolutionary processes. Restricted dispersal and locally occurring genetic drift are the primary causes for FSGS at equilibrium, as described in the isolation by distance (IBD) model. Beyond IBD expectations, spatial, environmental or historical factors can affect FSGS. We examined FSGS in seven African and Neotropical populations of the late-successional rain forest tree Symphonia globulifera L. f. (Clusiaceae) to discriminate the influence of drift-dispersal vs...
2017: PloS One
https://www.readbyqxmd.com/read/28770054/dispersal-corridors-for-plant-species-in-the-poyang-lake-basin-of-southeast-china-identified-by-integration-of-phylogeographic-and-geospatial-data
#15
Dengmei Fan, Zhixia Sun, Bo Li, Yixuan Kou, Richard G J Hodel, Zhinong Jin, Zhiyong Zhang
Measuring the dispersal of wildlife through landscapes is notoriously difficult. Recently, the categorical least cost path algorithm that integrates population genetic data with species distribution models has been applied to reveal population connectivity. In this study, we use this method to identify the possible dispersal corridors of five plant species (Castanopsis tibetana, Schima superba, Cyclocarya paliurus, Sargentodoxa cuneata, Eomecon chionantha) in the Poyang Lake Basin (PLB, largely coinciding with Jiangxi Province), China, in the late Quaternary...
July 2017: Ecology and Evolution
https://www.readbyqxmd.com/read/28770049/short-range-phenotypic-divergence-among-genetically-distinct-parapatric-populations-of-an-australian-funnel-web-spider
#16
Mark K L Wong, James D Woodman, David M Rowell
Speciation involves divergence at genetic and phenotypic levels. Where substantial genetic differentiation exists among populations, examining variation in multiple phenotypic characters may elucidate the mechanisms by which divergence and speciation unfold. Previous work on the Australian funnel-web spider Atrax sutherlandi Gray (2010; Records of the Australian Museum62, 285-392; Mygalomorphae: Hexathelidae: Atracinae) has revealed a marked genetic structure along a 110-kilometer transect, with six genetically distinct, parapatric populations attributable to past glacial cycles...
July 2017: Ecology and Evolution
https://www.readbyqxmd.com/read/28770047/consequences-of-population-topology-for-studying-gene-flow-using-link-based-landscape-genetic-methods
#17
Maarten J van Strien
Many landscape genetic studies aim to determine the effect of landscape on gene flow between populations. These studies frequently employ link-based methods that relate pairwise measures of historical gene flow to measures of the landscape and the geographical distance between populations. However, apart from landscape and distance, there is a third important factor that can influence historical gene flow, that is, population topology (i.e., the arrangement of populations throughout a landscape). As the population topology is determined in part by the landscape configuration, I argue that it should play a more prominent role in landscape genetics...
July 2017: Ecology and Evolution
https://www.readbyqxmd.com/read/28767419/b-lymphoblastic-leukemia-lymphoma-new-insights-into-genetics-molecular-aberrations-subclassification-and-targeted-therapy
#18
Xiaohui Zhang, Prerna Rastogi, Bijal Shah, Ling Zhang
B lymphoblastic leukemia/lymphoma (B-ALL) is a clonal hematopoietic stem cell neoplasm derived from B-cell progenitors, which mostly occurs in children and adolescents and is regarded as one of top leading causes of death related to malignancies in this population. Despite the majority of patients with B-ALL have fairly good response to conventional chemotherapeutic interventions followed by hematopoietic stem cell transplant for the last decades, a subpopulation of patients show chemo-resistance and a high relapse rate...
July 15, 2017: Oncotarget
https://www.readbyqxmd.com/read/28753846/the-landscape-of-whole-genome-alterations-and-pathologic-features-in-genitourinary-malignancies-an-analysis-of-the-cancer-genome-atlas
#19
Mark W Ball, Michael A Gorin, Charles G Drake, Hans J Hammers, Mohamad E Allaf
BACKGROUND: The accumulation of somatic genetic alterations drives carcinogenesis. Little is known, however, about how the level of genetic alteration across an entire cancer genome affects tumor grade, stage or survival. OBJECTIVE: To investigate the influence of somatic mutation count (MC) and copy number variation (CNV) on pathologic and oncologic outcomes in patients with genitourinary malignancies in The Cancer Genome Atlas (TCGA). DESIGN, SETTING, AND PARTICIPANTS: TCGA data sets for adrenocortical carcinoma (ACC), bladder urothelial carcinoma (BLCA), chromophobe renal cell carcinoma (RCC; KICH), clear cell RCC (KIRC), papillary RCC (KIRP), pheochromocytoma and paraganglioma (PCPG), prostate adenocarcinoma (PRAD), and testis germ cell tumor (TGCT) were accessed via cBioportal...
February 8, 2017: European Urology Focus
https://www.readbyqxmd.com/read/28753431/project-drive-a-compendium-of-cancer-dependencies-and-synthetic-lethal-relationships-uncovered-by-large-scale-deep-rnai-screening
#20
E Robert McDonald, Antoine de Weck, Michael R Schlabach, Eric Billy, Konstantinos J Mavrakis, Gregory R Hoffman, Dhiren Belur, Deborah Castelletti, Elizabeth Frias, Kalyani Gampa, Javad Golji, Iris Kao, Li Li, Philippe Megel, Thomas A Perkins, Nadire Ramadan, David A Ruddy, Serena J Silver, Sosathya Sovath, Mark Stump, Odile Weber, Roland Widmer, Jianjun Yu, Kristine Yu, Yingzi Yue, Dorothee Abramowski, Elizabeth Ackley, Rosemary Barrett, Joel Berger, Julie L Bernard, Rebecca Billig, Saskia M Brachmann, Frank Buxton, Roger Caothien, Justina X Caushi, Franklin S Chung, Marta Cortés-Cros, Rosalie S deBeaumont, Clara Delaunay, Aurore Desplat, William Duong, Donald A Dwoske, Richard S Eldridge, Ali Farsidjani, Fei Feng, JiaJia Feng, Daisy Flemming, William Forrester, Giorgio G Galli, Zhenhai Gao, François Gauter, Veronica Gibaja, Kristy Haas, Marc Hattenberger, Tami Hood, Kristen E Hurov, Zainab Jagani, Mathias Jenal, Jennifer A Johnson, Michael D Jones, Avnish Kapoor, Joshua Korn, Jilin Liu, Qiumei Liu, Shumei Liu, Yue Liu, Alice T Loo, Kaitlin J Macchi, Typhaine Martin, Gregory McAllister, Amandine Meyer, Sandra Mollé, Raymond A Pagliarini, Tanushree Phadke, Brian Repko, Tanja Schouwey, Frances Shanahan, Qiong Shen, Christelle Stamm, Christine Stephan, Volker M Stucke, Ralph Tiedt, Malini Varadarajan, Kavitha Venkatesan, Alberto C Vitari, Marco Wallroth, Jan Weiler, Jing Zhang, Craig Mickanin, Vic E Myer, Jeffery A Porter, Albert Lai, Hans Bitter, Emma Lees, Nicholas Keen, Audrey Kauffmann, Frank Stegmeier, Francesco Hofmann, Tobias Schmelzle, William R Sellers
Elucidation of the mutational landscape of human cancer has progressed rapidly and been accompanied by the development of therapeutics targeting mutant oncogenes. However, a comprehensive mapping of cancer dependencies has lagged behind and the discovery of therapeutic targets for counteracting tumor suppressor gene loss is needed. To identify vulnerabilities relevant to specific cancer subtypes, we conducted a large-scale RNAi screen in which viability effects of mRNA knockdown were assessed for 7,837 genes using an average of 20 shRNAs per gene in 398 cancer cell lines...
July 27, 2017: Cell
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