Publications by authors named "James O J Davies"

23 Publications

  • Page 1 of 1

Reactivation of a developmentally silenced embryonic globin gene.

Nat Commun 2021 07 21;12(1):4439. Epub 2021 Jul 21.

MRC Weatherall Institute of Molecular Medicine, University of Oxford, Oxford, UK.

The α- and β-globin loci harbor developmentally expressed genes, which are silenced throughout post-natal life. Reactivation of these genes may offer therapeutic approaches for the hemoglobinopathies, the most common single gene disorders. Here, we address mechanisms regulating the embryonically expressed α-like globin, termed ζ-globin. We show that in embryonic erythroid cells, the ζ-gene lies within a ~65 kb sub-TAD (topologically associating domain) of open, acetylated chromatin and interacts with the α-globin super-enhancer. By contrast, in adult erythroid cells, the ζ-gene is packaged within a small (~10 kb) sub-domain of hypoacetylated, facultative heterochromatin within the acetylated sub-TAD and that it no longer interacts with its enhancers. The ζ-gene can be partially re-activated by acetylation and inhibition of histone de-acetylases. In addition to suggesting therapies for severe α-thalassemia, these findings illustrate the general principles by which reactivation of developmental genes may rescue abnormalities arising from mutations in their adult paralogues.
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http://dx.doi.org/10.1038/s41467-021-24402-3DOI Listing
July 2021

Defining genome architecture at base-pair resolution.

Nature 2021 07 9;595(7865):125-129. Epub 2021 Jun 9.

MRC Molecular Haematology Unit, MRC Weatherall Institute of Molecular Medicine, Radcliffe Department of Medicine, University of Oxford, Oxford, UK.

In higher eukaryotes, many genes are regulated by enhancers that are 10-10 base pairs (bp) away from the promoter. Enhancers contain transcription-factor-binding sites (which are typically around 7-22 bp), and physical contact between the promoters and enhancers is thought to be required to modulate gene expression. Although chromatin architecture has been mapped extensively at resolutions of 1 kilobase and above; it has not been possible to define physical contacts at the scale of the proteins that determine gene expression. Here we define these interactions in detail using a chromosome conformation capture method (Micro-Capture-C) that enables the physical contacts between different classes of regulatory elements to be determined at base-pair resolution. We find that highly punctate contacts occur between enhancers, promoters and CCCTC-binding factor (CTCF) sites and we show that transcription factors have an important role in the maintenance of the contacts between enhancers and promoters. Our data show that interactions between CTCF sites are increased when active promoters and enhancers are located within the intervening chromatin. This supports a model in which chromatin loop extrusion is dependent on cohesin loading at active promoters and enhancers, which explains the formation of tissue-specific chromatin domains without changes in CTCF binding.
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http://dx.doi.org/10.1038/s41586-021-03639-4DOI Listing
July 2021

High-resolution targeted 3C interrogation of cis-regulatory element organization at genome-wide scale.

Nat Commun 2021 01 22;12(1):531. Epub 2021 Jan 22.

MRC Molecular Haematology Unit, MRC Weatherall Institute of Molecular Medicine, University of Oxford, Oxford, UK.

Chromosome conformation capture (3C) provides an adaptable tool for studying diverse biological questions. Current 3C methods generally provide either low-resolution interaction profiles across the entire genome, or high-resolution interaction profiles at limited numbers of loci. Due to technical limitations, generation of reproducible high-resolution interaction profiles has not been achieved at genome-wide scale. Here, to overcome this barrier, we systematically test each step of 3C and report two improvements over current methods. We show that up to 30% of reporter events generated using the popular in situ 3C method arise from ligations between two individual nuclei, but this noise can be almost entirely eliminated by isolating intact nuclei after ligation. Using Nuclear-Titrated Capture-C, we generate reproducible high-resolution genome-wide 3C interaction profiles by targeting 8055 gene promoters in erythroid cells. By pairing high-resolution 3C interaction calls with nascent gene expression we interrogate the role of promoter hubs and super-enhancers in gene regulation.
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http://dx.doi.org/10.1038/s41467-020-20809-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7822813PMC
January 2021

BET inhibition disrupts transcription but retains enhancer-promoter contact.

Nat Commun 2021 01 11;12(1):223. Epub 2021 Jan 11.

MRC Molecular Haematology Unit, MRC Weatherall Institute of Molecular Medicine, NIHR Oxford Biomedical Research Centre Haematology Theme, Radcliffe Department of Medicine, University of Oxford, Oxford, OX3 9DS, UK.

Enhancers are DNA sequences that enable complex temporal and tissue-specific regulation of genes in higher eukaryotes. Although it is not entirely clear how enhancer-promoter interactions can increase gene expression, this proximity has been observed in multiple systems at multiple loci and is thought to be essential for the maintenance of gene expression. Bromodomain and Extra-Terminal domain (BET) and Mediator proteins have been shown capable of forming phase condensates and are thought to be essential for super-enhancer function. Here, we show that targeting of cells with inhibitors of BET proteins or pharmacological degradation of BET protein Bromodomain-containing protein 4 (BRD4) has a strong impact on transcription but very little impact on enhancer-promoter interactions. Dissolving phase condensates reduces BRD4 and Mediator binding at enhancers and can also strongly affect gene transcription, without disrupting enhancer-promoter interactions. These results suggest that activation of transcription and maintenance of enhancer-promoter interactions are separable events. Our findings further indicate that enhancer-promoter interactions are not dependent on high levels of BRD4 and Mediator, and are likely maintained by a complex set of factors including additional activator complexes and, at some sites, CTCF and cohesin.
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http://dx.doi.org/10.1038/s41467-020-20400-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7801379PMC
January 2021

Loss of Extreme Long-Range Enhancers in Human Neural Crest Drives a Craniofacial Disorder.

Cell Stem Cell 2020 11 28;27(5):765-783.e14. Epub 2020 Sep 28.

Department of Chemical and Systems Biology, Stanford University School of Medicine, Stanford, CA 94305, USA; Department of Developmental Biology, Stanford University School of Medicine, Stanford, CA 94305, USA; Institute of Stem Cell Biology and Regenerative Medicine, Stanford University School of Medicine, Stanford, CA 94305, USA; Howard Hughes Medical Institute, Stanford University School of Medicine, Stanford, CA 94305, USA. Electronic address:

Non-coding mutations at the far end of a large gene desert surrounding the SOX9 gene result in a human craniofacial disorder called Pierre Robin sequence (PRS). Leveraging a human stem cell differentiation model, we identify two clusters of enhancers within the PRS-associated region that regulate SOX9 expression during a restricted window of facial progenitor development at distances up to 1.45 Mb. Enhancers within the 1.45 Mb cluster exhibit highly synergistic activity that is dependent on the Coordinator motif. Using mouse models, we demonstrate that PRS phenotypic specificity arises from the convergence of two mechanisms: confinement of Sox9 dosage perturbation to developing facial structures through context-specific enhancer activity and heightened sensitivity of the lower jaw to Sox9 expression reduction. Overall, we characterize the longest-range human enhancers involved in congenital malformations, directly demonstrate that PRS is an enhanceropathy, and illustrate how small changes in gene expression can lead to morphological variation.
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http://dx.doi.org/10.1016/j.stem.2020.09.001DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7655526PMC
November 2020

Single-allele chromatin interactions identify regulatory hubs in dynamic compartmentalized domains.

Nat Genet 2018 12 29;50(12):1744-1751. Epub 2018 Oct 29.

MRC Molecular Haematology Unit, MRC Weatherall Institute of Molecular Medicine, Radcliffe Department of Medicine, University of Oxford, Oxford, UK.

The promoters of mammalian genes are commonly regulated by multiple distal enhancers, which physically interact within discrete chromatin domains. How such domains form and how the regulatory elements within them interact in single cells is not understood. To address this we developed Tri-C, a new chromosome conformation capture (3C) approach, to characterize concurrent chromatin interactions at individual alleles. Analysis by Tri-C identifies heterogeneous patterns of single-allele interactions between CTCF boundary elements, indicating that the formation of chromatin domains likely results from a dynamic process. Within these domains, we observe specific higher-order structures that involve simultaneous interactions between multiple enhancers and promoters. Such regulatory hubs provide a structural basis for understanding how multiple cis-regulatory elements act together to establish robust regulation of gene expression.
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http://dx.doi.org/10.1038/s41588-018-0253-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6265079PMC
December 2018

HoxC5 and miR-615-3p target newly evolved genomic regions to repress hTERT and inhibit tumorigenesis.

Nat Commun 2018 01 8;9(1):100. Epub 2018 Jan 8.

Cancer and Stem Cell Biology Program, Duke-NUS Medical School, 8 College Road, Singapore, 169857, Singapore.

The repression of telomerase activity during cellular differentiation promotes replicative aging and functions as a physiological barrier for tumorigenesis in long-lived mammals, including humans. However, the underlying mechanisms remain largely unclear. Here we describe how miR-615-3p represses hTERT expression. mir-615-3p is located in an intron of the HOXC5 gene, a member of the highly conserved homeobox family of transcription factors controlling embryogenesis and development. Unexpectedly, we found that HoxC5 also represses hTERT expression by disrupting the long-range interaction between hTERT promoter and its distal enhancer. The 3'UTR of hTERT and its upstream enhancer region are well conserved in long-lived primates. Both mir-615-3p and HOXC5 are activated upon differentiation, which constitute a feed-forward loop that coordinates transcriptional and post-transcriptional repression of hTERT during cellular differentiation. Deregulation of HOXC5 and mir-615-3p expression may contribute to the activation of hTERT in human cancers.
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http://dx.doi.org/10.1038/s41467-017-02601-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5758779PMC
January 2018

Low-input Capture-C: A Chromosome Conformation Capture Assay to Analyze Chromatin Architecture in Small Numbers of Cells.

Bio Protoc 2017 Dec;7(23)

Medical Research Council (MRC) Molecular Haematology Unit, Weatherall Institute of Molecular Medicine, University of Oxford, Oxford, United Kingdom.

Chromosome conformation capture (3C) techniques are crucial to understanding tissue-specific regulation of gene expression, but current methods generally require large numbers of cells. This protocol describes two new low-input Capture-C approaches that can generate high-quality 3C interaction profiles from 10,000-20,000 cells, depending on the resolution used for analysis.
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http://dx.doi.org/10.21769/BioProtoc.2645DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5736099PMC
December 2017

Macrophage activation syndrome and post-transplant microangiopathy following haploidentical bone marrow transplantation for sickle cell anemia.

Am J Hematol 2018 08 18;93(4):588-589. Epub 2017 Dec 18.

St Mary's Hospital, Imperial College Healthcare NHS Foundation Trust, Praed Street, London, W2 1NY, United Kingdom.

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http://dx.doi.org/10.1002/ajh.24995DOI Listing
August 2018

Robust detection of chromosomal interactions from small numbers of cells using low-input Capture-C.

Nucleic Acids Res 2017 Dec;45(22):e184

Medical Research Council (MRC) Molecular Haematology Unit, Weatherall Institute of Molecular Medicine, University of Oxford, Oxford OX3 9DS, UK.

Chromosome conformation capture (3C) techniques are crucial to understanding tissue-specific regulation of gene expression, but current methods generally require large numbers of cells. This hampers the investigation of chromatin architecture in rare cell populations. We present a new low-input Capture-C approach that can generate high-quality 3C interaction profiles from 10 000-20 000 cells, depending on the resolution used for analysis. We also present a PCR-free, sequencing-free 3C technique based on NanoString technology called C-String. By comparing C-String and Capture-C interaction profiles we show that the latter are not skewed by PCR amplification. Furthermore, we demonstrate that chromatin interactions detected by Capture-C do not depend on the degree of cross-linking by performing experiments with varying formaldehyde concentrations.
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http://dx.doi.org/10.1093/nar/gkx1194DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5728395PMC
December 2017

Comparative analysis of three-dimensional chromosomal architecture identifies a novel fetal hemoglobin regulatory element.

Genes Dev 2017 08 15;31(16):1704-1713. Epub 2017 Sep 15.

Division of Hematology, The Children's Hospital of Philadelphia, Philadelphia, Pennsylvania 19104, USA.

Chromatin structure is tightly intertwined with transcription regulation. Here we compared the chromosomal architectures of fetal and adult human erythroblasts and found that, globally, chromatin structures and compartments A/B are highly similar at both developmental stages. At a finer scale, we detected distinct folding patterns at the developmentally controlled β-globin locus. Specifically, new fetal stage-specific contacts were uncovered between a region separating the fetal (γ) and adult (δ and β) globin genes (encompassing the and noncoding genes) and two distal chromosomal sites (HS5 and 3'HS1) that flank the locus. In contrast, in adult cells, the - region contacts the embryonic ε-globin gene, physically separating the fetal globin genes from the enhancer (locus control region [LCR]). Deletion of the region in adult cells alters contact landscapes in ways more closely resembling those of fetal cells, including increased LCR-γ-globin contacts. These changes are accompanied by strong increases in γ-globin transcription. Notably, the effects of removal on chromatin architecture and gene expression closely mimic those of deleting the fetal globin repressor BCL11A, implicating BCL11A in the function of the region. Our results uncover a new critical regulatory region as a potential target for therapeutic genome editing for hemoglobinopathies and highlight the power of chromosome conformation analysis in discovering new control elements.
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http://dx.doi.org/10.1101/gad.303461.117DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5647940PMC
August 2017

Deficiency Drives Enhancer Activation of Oncogenes in Clear Cell Renal Cell Carcinoma.

Cancer Discov 2017 11 11;7(11):1284-1305. Epub 2017 Sep 11.

Cancer Therapeutics and Stratified Oncology, Genome Institute of Singapore, Singapore.

Protein-coding mutations in clear cell renal cell carcinoma (ccRCC) have been extensively characterized, frequently involving inactivation of the von Hippel-Lindau () tumor suppressor. Roles for noncoding -regulatory aberrations in ccRCC tumorigenesis, however, remain unclear. Analyzing 10 primary tumor/normal pairs and 9 cell lines across 79 chromatin profiles, we observed pervasive enhancer malfunction in ccRCC, with cognate enhancer-target genes associated with tissue-specific aspects of malignancy. Superenhancer profiling identified as a ccRCC-specific and VHL-regulated master regulator whose depletion causes near-complete tumor elimination and loss predominantly drives enhancer/superenhancer deregulation more so than promoters, with acquisition of active enhancer marks (H3K27ac, H3K4me1) near ccRCC hallmark genes. Mechanistically, VHL loss stabilizes HIF2α-HIF1β heterodimer binding at enhancers, subsequently recruiting histone acetyltransferase p300 without overtly affecting preexisting promoter-enhancer interactions. Subtype-specific driver mutations such as may thus propagate unique pathogenic dependencies in ccRCC by modulating epigenomic landscapes and cancer gene expression. Comprehensive epigenomic profiling of ccRCC establishes a compendium of somatically altered -regulatory elements, uncovering new potential targets including ZNF395, a ccRCC master regulator. Loss of , a ccRCC signature event, causes pervasive enhancer malfunction, with binding of enhancer-centric HIF2α and recruitment of histone acetyltransferase p300 at preexisting lineage-specific promoter-enhancer complexes. .
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http://dx.doi.org/10.1158/2159-8290.CD-17-0375DOI Listing
November 2017

How best to identify chromosomal interactions: a comparison of approaches.

Nat Methods 2017 01;14(2):125-134

Medical Research Council (MRC) Molecular Hematology Unit, Weatherall Institute of Molecular Medicine, Oxford University, Oxford, United Kingdom.

Chromosome conformation capture (3C) methods are central to understanding the link between nuclear structure and function, and the physical interactions between distal regulatory elements and promoters. However, no one method is appropriate to address all biological questions, as each variant differs markedly in resolution, reproducibility, throughput and biases. A thorough appreciation of the strengths and weaknesses of each technique is critical when choosing the correct method for a specific application or for gauging how best to interpret different sources of data. In addition, the analysis method must be carefully considered, as this choice can profoundly affect the output. In this Review, we describe and compare the different available 3C-based approaches, with a focus on the analysis of mammalian genomes.
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http://dx.doi.org/10.1038/nmeth.4146DOI Listing
January 2017

MLL-AF4 binds directly to a BCL-2 specific enhancer and modulates H3K27 acetylation.

Exp Hematol 2017 03 14;47:64-75. Epub 2016 Nov 14.

Weatherall Institute of Molecular Medicine, MRC Molecular Haematology Unit, University of Oxford, Headington, Oxford, UK. Electronic address:

Survival rates for children and adults carrying mutations in the Mixed Lineage Leukemia (MLL) gene continue to have a very poor prognosis. The most common MLL mutation in acute lymphoblastic leukemia is the t(4;11)(q21;q23) chromosome translocation that fuses MLL in-frame with the AF4 gene producing MLL-AF4 and AF4-MLL fusion proteins. Previously, we found that MLL-AF4 binds to the BCL-2 gene and directly activates it through DOT1L recruitment and increased H3K79me2/3 levels. In the study described here, we performed a detailed analysis of MLL-AF4 regulation of the entire BCL-2 family. By measuring nascent RNA production in MLL-AF4 knockdowns, we found that of all the BCL-2 family genes, MLL-AF4 directly controls the active transcription of both BCL-2 and MCL-1 and also represses BIM via binding of the polycomb group repressor 1 (PRC1) complex component CBX8. We further analyzed MLL-AF4 activation of the BCL-2 gene using Capture-C and identified a BCL-2-specific enhancer, consisting of two clusters of H3K27Ac at the 3' end of the gene. Loss of MLL-AF4 activity results in a reduction of H3K79me3 levels in the gene body and H3K27Ac levels at the 3' BCL-2 enhancer, revealing a novel regulatory link between these two histone marks and MLL-AF4-mediated activation of BCL-2.
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http://dx.doi.org/10.1016/j.exphem.2016.11.003DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5333536PMC
March 2017

Epigenomic profiling of primary gastric adenocarcinoma reveals super-enhancer heterogeneity.

Nat Commun 2016 Sep 28;7:12983. Epub 2016 Sep 28.

Medical Research Council (MRC) Molecular Haematology Unit, Weatherall Institute of Molecular Medicine, Oxford University, Oxford OX3 9DS, UK.

Regulatory enhancer elements in solid tumours remain poorly characterized. Here we apply micro-scale chromatin profiling to survey the distal enhancer landscape of primary gastric adenocarcinoma (GC), a leading cause of global cancer mortality. Integrating 110 epigenomic profiles from primary GCs, normal gastric tissues and cell lines, we highlight 36,973 predicted enhancers and 3,759 predicted super-enhancers respectively. Cell-line-defined super-enhancers can be subclassified by their somatic alteration status into somatic gain, loss and unaltered categories, each displaying distinct epigenetic, transcriptional and pathway enrichments. Somatic gain super-enhancers are associated with complex chromatin interaction profiles, expression patterns correlated with patient outcome and dense co-occupancy of the transcription factors CDX2 and HNF4α. Somatic super-enhancers are also enriched in genetic risk SNPs associated with cancer predisposition. Our results reveal a genome-wide reprogramming of the GC enhancer and super-enhancer landscape during tumorigenesis, contributing to dysregulated local and regional cancer gene expression.
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http://dx.doi.org/10.1038/ncomms12983DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5052795PMC
September 2016

Genetic dissection of the α-globin super-enhancer in vivo.

Nat Genet 2016 08 4;48(8):895-903. Epub 2016 Jul 4.

MRC Molecular Haematology Unit, Weatherall Institute of Molecular Medicine, Oxford, UK.

Many genes determining cell identity are regulated by clusters of Mediator-bound enhancer elements collectively referred to as super-enhancers. These super-enhancers have been proposed to manifest higher-order properties important in development and disease. Here we report a comprehensive functional dissection of one of the strongest putative super-enhancers in erythroid cells. By generating a series of mouse models, deleting each of the five regulatory elements of the α-globin super-enhancer individually and in informative combinations, we demonstrate that each constituent enhancer seems to act independently and in an additive fashion with respect to hematological phenotype, gene expression, chromatin structure and chromosome conformation, without clear evidence of synergistic or higher-order effects. Our study highlights the importance of functional genetic analyses for the identification of new concepts in transcriptional regulation.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5058437PMC
http://dx.doi.org/10.1038/ng.3605DOI Listing
August 2016

Unlinking an lncRNA from Its Associated cis Element.

Mol Cell 2016 Apr 31;62(1):104-10. Epub 2016 Mar 31.

Department of Hematology, St. Jude Children's Research Hospital, Memphis, TN 38105, USA. Electronic address:

Long non-coding (lnc) RNAs can regulate gene expression and protein functions. However, the proportion of lncRNAs with biological activities among the thousands expressed in mammalian cells is controversial. We studied Lockd (lncRNA downstream of Cdkn1b), a 434-nt polyadenylated lncRNA originating 4 kb 3' to the Cdkn1b gene. Deletion of the 25-kb Lockd locus reduced Cdkn1b transcription by approximately 70% in an erythroid cell line. In contrast, homozygous insertion of a polyadenylation cassette 80 bp downstream of the Lockd transcription start site reduced the entire lncRNA transcript level by >90% with no effect on Cdkn1b transcription. The Lockd promoter contains a DNase-hypersensitive site, binds numerous transcription factors, and physically associates with the Cdkn1b promoter in chromosomal conformation capture studies. Therefore, the Lockd gene positively regulates Cdkn1b transcription through an enhancer-like cis element, whereas the lncRNA itself is dispensable, which may be the case for other lncRNAs.
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http://dx.doi.org/10.1016/j.molcel.2016.02.029DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4877494PMC
April 2016

Multiplexed analysis of chromosome conformation at vastly improved sensitivity.

Nat Methods 2016 Jan 23;13(1):74-80. Epub 2015 Nov 23.

Medical Research Council, Molecular Haematology Unit, Weatherall Institute of Molecular Medicine, Oxford University, Oxford, UK.

Methods for analyzing chromosome conformation in mammalian cells are either low resolution or low throughput and are technically challenging. In next-generation (NG) Capture-C, we have redesigned the Capture-C method to achieve unprecedented levels of sensitivity and reproducibility. NG Capture-C can be used to analyze many genetic loci and samples simultaneously. High-resolution data can be produced with as few as 100,000 cells, and single-nucleotide polymorphisms can be used to generate allele-specific tracks. The method is straightforward to perform and should greatly facilitate the investigation of many questions related to gene regulation as well as the functional dissection of traits examined in genome-wide association studies.
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http://dx.doi.org/10.1038/nmeth.3664DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4724891PMC
January 2016

Respiratory complications of organophosphorus nerve agent and insecticide poisoning. Implications for respiratory and critical care.

Am J Respir Crit Care Med 2014 Dec;190(12):1342-54

1 Pharmacology, Toxicology, and Therapeutics, University/BHF Centre for Cardiovascular Science, University of Edinburgh, Edinburgh, United Kingdom.

Organophosphorus (OP) compound poisoning is a major global public health problem. Acute OP insecticide self-poisoning kills over 200,000 people every year, the majority from self-harm in rural Asia. Highly toxic OP nerve agents (e.g., sarin) are a significant current terrorist threat, as shown by attacks in Damascus during 2013. These anticholinesterase compounds are classically considered to cause an acute cholinergic syndrome with decreased consciousness, respiratory failure, and, in the case of insecticides, a delayed intermediate syndrome that requires prolonged ventilation. Acute respiratory failure, by central and peripheral mechanisms, is the primary cause of death in most cases. However, preclinical and clinical research over the last two decades has indicated a more complex picture of respiratory complications after OP insecticide poisoning, including onset of delayed neuromuscular junction dysfunction during the cholinergic syndrome, aspiration causing pneumonia and acute respiratory distress syndrome, and the involvement of solvents in OP toxicity. The treatment of OP poisoning has not changed over the last 50 years. However, a better understanding of the multiple respiratory complications of OP poisoning offers additional therapeutic opportunities.
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http://dx.doi.org/10.1164/rccm.201406-1150CIDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4299648PMC
December 2014

Opportunities and limitations of natural killer cells as adoptive therapy for malignant disease.

Cytotherapy 2014 Nov 20;16(11):1453-1466. Epub 2014 May 20.

Stem Cell Transplantation and Cellular Therapy, MD Anderson Cancer Center, Houston, Texas, USA. Electronic address:

Although natural killer (NK) cells can be readily generated for adoptive therapy with current techniques, their optimal application to treat malignant diseases requires an appreciation of the dynamic balance between signals that either synergize with or antagonize each other. Individuals display wide differences in NK function that determine their therapeutic efficacy. The ability of NK cells to kill target cells or produce cytokines depends on the balance between signals from activating and inhibitory cell-surface receptors. The selection of NK cells with a predominant activating profile is critical for delivering successful anti-tumor activity. This can be achieved through selection of killer immunoglobulin-like receptor-mismatched NK donors and by use of blocking molecules against inhibitory pathways. Optimum NK cytotoxicity may require licensing or priming with tumor cells. Recent discoveries in the molecular and cellular biology of NK cells inform in the design of new strategies, including adjuvant therapies, to maximize the cytotoxic potential of NK cells for adoptive transfer to treat human malignancies.
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http://dx.doi.org/10.1016/j.jcyt.2014.03.009DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4190023PMC
November 2014

Oral C-4 plastic explosive in humans - a case series.

Clin Toxicol (Phila) 2007 Jun-Aug;45(5):454-7

South Asian Clinical Toxicology Research Collaboration Clinical Unit, Anuradhapura General Hospital, North Central Province, Sri Lanka.

Introduction: C-4 is a plastic explosive widely used for demolition in both military and civilian settings. Severe toxicity following unintentional oral exposures or abuse have been reported in single case reports and small case series.

Case Series: Seventeen previously healthy male Army commandos admitted to a secondary referral hospital in Sri Lanka following oral C-4 poisoning.

Methods: This data was collected as part of a prospective cohort study recruiting all patients admitted to general hospitals in Sri Lanka with a history of poisoning. History, clinical, and laboratory outcomes were recorded until discharge.

Results: All 17 patients survived. The prominent clinical features were seizures, headache, nausea, and vomiting. Hypokalaemia and elevation of creatine kinase, lactate dehydrogenase, and phosphate were noted in all but two patients. Metabolic acidosis occurred in two patients following seizures and this resolved spontaneously.

Conclusions: Management recommendations include standard resuscitation, supportive care, and benzodiazepines for the control of seizures or agitation. Poisoning with C-4 is an unusual cause of seizures which should be considered in patients with access to this agent.
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http://dx.doi.org/10.1080/15563650601118044DOI Listing
July 2007