Publications by authors named "Matthew D Young"

42 Publications

Tumor to normal single-cell mRNA comparisons reveal a pan-neuroblastoma cancer cell.

Sci Adv 2021 Feb 5;7(6). Epub 2021 Feb 5.

Wellcome Sanger Institute, CB10 1SA Hinxton, UK.

Neuroblastoma is a childhood cancer that resembles developmental stages of the neural crest. It is not established what developmental processes neuroblastoma cancer cells represent. Here, we sought to reveal the phenotype of neuroblastoma cancer cells by comparing cancer ( = 19,723) with normal fetal adrenal single-cell transcriptomes ( = 57,972). Our principal finding was that the neuroblastoma cancer cell resembled fetal sympathoblasts, but no other fetal adrenal cell type. The sympathoblastic state was a universal feature of neuroblastoma cells, transcending cell cluster diversity, individual patients, and clinical phenotypes. We substantiated our findings in 650 neuroblastoma bulk transcriptomes and by integrating canonical features of the neuroblastoma genome with transcriptional signals. Overall, our observations indicate that a pan-neuroblastoma cancer cell state exists, which may be attractive for novel immunotherapeutic and targeted avenues.
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http://dx.doi.org/10.1126/sciadv.abd3311DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7864567PMC
February 2021

Pitfalls of Applying Mouse Markers to Human Adrenal Medullary Cells.

Cancer Cell 2021 Feb 31;39(2):132-133. Epub 2020 Dec 31.

Wellcome Sanger Institute, Hinxton CB10 1SA, UK; Cambridge University Hospitals NHS Foundation Trust, Cambridge CB2 0QQ, UK; Department of Paediatrics, University of Cambridge, Cambridge CB2 0QQ, UK. Electronic address:

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http://dx.doi.org/10.1016/j.ccell.2020.12.006DOI Listing
February 2021

SoupX removes ambient RNA contamination from droplet-based single-cell RNA sequencing data.

Gigascience 2020 Dec;9(12)

Wellcome Trust Sanger Institute, Cellular Genetics, Wellcome Genome Campus, Hinxton, CB10 1SA, UK.

Background: Droplet-based single-cell RNA sequence analyses assume that all acquired RNAs are endogenous to cells. However, any cell-free RNAs contained within the input solution are also captured by these assays. This sequencing of cell-free RNA constitutes a background contamination that confounds the biological interpretation of single-cell transcriptomic data.

Results: We demonstrate that contamination from this "soup" of cell-free RNAs is ubiquitous, with experiment-specific variations in composition and magnitude. We present a method, SoupX, for quantifying the extent of the contamination and estimating "background-corrected" cell expression profiles that seamlessly integrate with existing downstream analysis tools. Applying this method to several datasets using multiple droplet sequencing technologies, we demonstrate that its application improves biological interpretation of otherwise misleading data, as well as improving quality control metrics.

Conclusions: We present SoupX, a tool for removing ambient RNA contamination from droplet-based single-cell RNA sequencing experiments. This tool has broad applicability, and its application can improve the biological utility of existing and future datasets.
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http://dx.doi.org/10.1093/gigascience/giaa151DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7763177PMC
December 2020

Single-cell atlas of the first intra-mammalian developmental stage of the human parasite Schistosoma mansoni.

Nat Commun 2020 12 18;11(1):6411. Epub 2020 Dec 18.

Wellcome Sanger Institute, Wellcome Genome Campus, Hinxton, Cambridgeshire, UK.

Over 250 million people suffer from schistosomiasis, a tropical disease caused by parasitic flatworms known as schistosomes. Humans become infected by free-swimming, water-borne larvae, which penetrate the skin. The earliest intra-mammalian stage, called the schistosomulum, undergoes a series of developmental transitions. These changes are critical for the parasite to adapt to its new environment as it navigates through host tissues to reach its niche, where it will grow to reproductive maturity. Unravelling the mechanisms that drive intra-mammalian development requires knowledge of the spatial organisation and transcriptional dynamics of different cell types that comprise the schistomulum body. To fill these important knowledge gaps, we perform single-cell RNA sequencing on two-day old schistosomula of Schistosoma mansoni. We identify likely gene expression profiles for muscle, nervous system, tegument, oesophageal gland, parenchymal/primordial gut cells, and stem cells. In addition, we validate cell markers for all these clusters by in situ hybridisation in schistosomula and adult parasites. Taken together, this study provides a comprehensive cell-type atlas for the early intra-mammalian stage of this devastating metazoan parasite.
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http://dx.doi.org/10.1038/s41467-020-20092-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7749135PMC
December 2020

Single-cell sequencing reveals clonal expansions of pro-inflammatory synovial CD8 T cells expressing tissue-homing receptors in psoriatic arthritis.

Nat Commun 2020 09 21;11(1):4767. Epub 2020 Sep 21.

Nuffield Department of Orthopaedics Rheumatology and Musculoskeletal Sciences, University of Oxford, Oxford, OX3 7LD, UK.

Psoriatic arthritis (PsA) is a debilitating immune-mediated inflammatory arthritis of unknown pathogenesis commonly affecting patients with skin psoriasis. Here we use complementary single-cell approaches to study leukocytes from PsA joints. Mass cytometry demonstrates a 3-fold expansion of memory CD8 T cells in the joints of PsA patients compared to peripheral blood. Meanwhile, droplet-based and plate-based single-cell RNA sequencing of paired T cell receptor alpha and beta chain sequences show pronounced CD8 T cell clonal expansions within the joints. Transcriptome analyses find these expanded synovial CD8 T cells to express cycling, activation, tissue-homing and tissue residency markers. T cell receptor sequence comparison between patients identifies clonal convergence. Finally, chemokine receptor CXCR3 is upregulated in the expanded synovial CD8 T cells, while two CXCR3 ligands, CXCL9 and CXCL10, are elevated in PsA synovial fluid. Our data thus provide a quantitative molecular insight into the cellular immune landscape of psoriatic arthritis.
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http://dx.doi.org/10.1038/s41467-020-18513-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7505844PMC
September 2020

Embryonal precursors of Wilms tumor.

Science 2019 12;366(6470):1247-1251

Wellcome Sanger Institute, Hinxton CB10 1SA, UK.

Adult cancers often arise from premalignant clonal expansions. Whether the same is true of childhood tumors has been unclear. To investigate whether Wilms tumor (nephroblastoma; a childhood kidney cancer) develops from a premalignant background, we examined the phylogenetic relationship between tumors and corresponding normal tissues. In 14 of 23 cases studied (61%), we found premalignant clonal expansions in morphologically normal kidney tissues that preceded tumor development. These clonal expansions were defined by somatic mutations shared between tumor and normal tissues but absent from blood cells. We also found hypermethylation of the locus, a known driver of Wilms tumor development, in 58% of the expansions. Phylogenetic analyses of bilateral tumors indicated that clonal expansions can evolve before the divergence of left and right kidney primordia. These findings reveal embryonal precursors from which unilateral and multifocal cancers develop.
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http://dx.doi.org/10.1126/science.aax1323DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6914378PMC
December 2019

Spatiotemporal immune zonation of the human kidney.

Science 2019 09;365(6460):1461-1466

Molecular Immunity Unit, Department of Medicine, University of Cambridge, Cambridge CB2 0QQ, UK.

Tissue-resident immune cells are important for organ homeostasis and defense. The epithelium may contribute to these functions directly or by cross-talk with immune cells. We used single-cell RNA sequencing to resolve the spatiotemporal immune topology of the human kidney. We reveal anatomically defined expression patterns of immune genes within the epithelial compartment, with antimicrobial peptide transcripts evident in pelvic epithelium in the mature, but not fetal, kidney. A network of tissue-resident myeloid and lymphoid immune cells was evident in both fetal and mature kidney, with postnatal acquisition of transcriptional programs that promote infection-defense capabilities. Epithelial-immune cross-talk orchestrated localization of antibacterial macrophages and neutrophils to the regions of the kidney most susceptible to infection. Overall, our study provides a global overview of how the immune landscape of the human kidney is zonated to counter the dominant immunological challenge.
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http://dx.doi.org/10.1126/science.aat5031DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7343525PMC
September 2019

Decoding human fetal liver haematopoiesis.

Nature 2019 10 9;574(7778):365-371. Epub 2019 Oct 9.

Institute of Cellular Medicine, Newcastle University, Newcastle upon Tyne, UK.

Definitive haematopoiesis in the fetal liver supports self-renewal and differentiation of haematopoietic stem cells and multipotent progenitors (HSC/MPPs) but remains poorly defined in humans. Here, using single-cell transcriptome profiling of approximately 140,000 liver and 74,000 skin, kidney and yolk sac cells, we identify the repertoire of human blood and immune cells during development. We infer differentiation trajectories from HSC/MPPs and evaluate the influence of the tissue microenvironment on blood and immune cell development. We reveal physiological erythropoiesis in fetal skin and the presence of mast cells, natural killer and innate lymphoid cell precursors in the yolk sac. We demonstrate a shift in the haemopoietic composition of fetal liver during gestation away from being predominantly erythroid, accompanied by a parallel change in differentiation potential of HSC/MPPs, which we functionally validate. Our integrated map of fetal liver haematopoiesis provides a blueprint for the study of paediatric blood and immune disorders, and a reference for harnessing the therapeutic potential of HSC/MPPs.
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http://dx.doi.org/10.1038/s41586-019-1652-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6861135PMC
October 2019

BBKNN: fast batch alignment of single cell transcriptomes.

Bioinformatics 2020 02;36(3):964-965

Cellular Genetics, Wellcome Sanger Institute, Hinxton, Cambridge CB10 1SA, UK.

Motivation: Increasing numbers of large scale single cell RNA-Seq projects are leading to a data explosion, which can only be fully exploited through data integration. A number of methods have been developed to combine diverse datasets by removing technical batch effects, but most are computationally intensive. To overcome the challenge of enormous datasets, we have developed BBKNN, an extremely fast graph-based data integration algorithm. We illustrate the power of BBKNN on large scale mouse atlasing data, and favourably benchmark its run time against a number of competing methods.

Availability And Implementation: BBKNN is available at https://github.com/Teichlab/bbknn, along with documentation and multiple example notebooks, and can be installed from pip.

Supplementary Information: Supplementary data are available at Bioinformatics online.
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http://dx.doi.org/10.1093/bioinformatics/btz625DOI Listing
February 2020

An integrated genomic analysis of anaplastic meningioma identifies prognostic molecular signatures.

Sci Rep 2018 09 10;8(1):13537. Epub 2018 Sep 10.

Wellcome Sanger Institute, Wellcome Genome Campus, Hinxton, CB10 1SA, UK.

Anaplastic meningioma is a rare and aggressive brain tumor characterised by intractable recurrences and dismal outcomes. Here, we present an integrated analysis of the whole genome, transcriptome and methylation profiles of primary and recurrent anaplastic meningioma. A key finding was the delineation of distinct molecular subgroups that were associated with diametrically opposed survival outcomes. Relative to lower grade meningiomas, anaplastic tumors harbored frequent driver mutations in SWI/SNF complex genes, which were confined to the poor prognosis subgroup. Aggressive disease was further characterised by transcriptional evidence of increased PRC2 activity, stemness and epithelial-to-mesenchymal transition. Our analyses discern biologically distinct variants of anaplastic meningioma with prognostic and therapeutic significance.
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http://dx.doi.org/10.1038/s41598-018-31659-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6131140PMC
September 2018

Rearrangement bursts generate canonical gene fusions in bone and soft tissue tumors.

Science 2018 08;361(6405)

Program in Genetics and Genome Biology, The Hospital for Sick Children, Toronto, Ontario, Canada.

Sarcomas are cancers of the bone and soft tissue often defined by gene fusions. Ewing sarcoma involves fusions between , a gene encoding an RNA binding protein, and E26 transformation-specific (ETS) transcription factors. We explored how and when fusions arise by studying the whole genomes of Ewing sarcomas. In 52 of 124 (42%) of tumors, the fusion gene arises by a sudden burst of complex, loop-like rearrangements, a process called chromoplexy, rather than by simple reciprocal translocations. These loops always contained the disease-defining fusion at the center, but they disrupted multiple additional genes. The loops occurred preferentially in early replicating and transcriptionally active genomic regions. Similar loops forming canonical fusions were found in three other sarcoma types. Chromoplexy-generated fusions appear to be associated with an aggressive form of Ewing sarcoma. These loops arise early, giving rise to both primary and relapse Ewing sarcoma tumors, which can continue to evolve in parallel.
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http://dx.doi.org/10.1126/science.aam8419DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6176908PMC
August 2018

Single-cell transcriptomes from human kidneys reveal the cellular identity of renal tumors.

Science 2018 08;361(6402):594-599

Wellcome Sanger Institute, Hinxton CB10 1SA, UK.

Messenger RNA encodes cellular function and phenotype. In the context of human cancer, it defines the identities of malignant cells and the diversity of tumor tissue. We studied 72,501 single-cell transcriptomes of human renal tumors and normal tissue from fetal, pediatric, and adult kidneys. We matched childhood Wilms tumor with specific fetal cell types, thus providing evidence for the hypothesis that Wilms tumor cells are aberrant fetal cells. In adult renal cell carcinoma, we identified a canonical cancer transcriptome that matched a little-known subtype of proximal convoluted tubular cell. Analyses of the tumor composition defined cancer-associated normal cells and delineated a complex vascular endothelial growth factor (VEGF) signaling circuit. Our findings reveal the precise cellular identities and compositions of human kidney tumors.
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http://dx.doi.org/10.1126/science.aat1699DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6104812PMC
August 2018

Recurrent rearrangements of FOS and FOSB define osteoblastoma.

Nat Commun 2018 06 1;9(1):2150. Epub 2018 Jun 1.

Wellcome Trust Sanger Institute, Hinxton, Cambridgeshire, CB10 1SA, UK.

The transcription factor FOS has long been implicated in the pathogenesis of bone tumours, following the discovery that the viral homologue, v-fos, caused osteosarcoma in laboratory mice. However, mutations of FOS have not been found in human bone-forming tumours. Here, we report recurrent rearrangement of FOS and its paralogue, FOSB, in the most common benign tumours of bone, osteoblastoma and osteoid osteoma. Combining whole-genome DNA and RNA sequences, we find rearrangement of FOS in five tumours and of FOSB in one tumour. Extending our findings into a cohort of 55 cases, using FISH and immunohistochemistry, provide evidence of ubiquitous mutation of FOS or FOSB in osteoblastoma and osteoid osteoma. Overall, our findings reveal a human bone tumour defined by mutations of FOS and FOSB.
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http://dx.doi.org/10.1038/s41467-018-04530-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5984627PMC
June 2018

Intra-tumour diversification in colorectal cancer at the single-cell level.

Nature 2018 04 11;556(7702):457-462. Epub 2018 Apr 11.

Hubrecht Institute, University Medical Center Utrecht and Princess Maxima Center, Utrecht, The Netherlands.

Every cancer originates from a single cell. During expansion of the neoplastic cell population, individual cells acquire genetic and phenotypic differences from each other. Here, to investigate the nature and extent of intra-tumour diversification, we characterized organoids derived from multiple single cells from three colorectal cancers as well as from adjacent normal intestinal crypts. Colorectal cancer cells showed extensive mutational diversification and carried several times more somatic mutations than normal colorectal cells. Most mutations were acquired during the final dominant clonal expansion of the cancer and resulted from mutational processes that are absent from normal colorectal cells. Intra-tumour diversification of DNA methylation and transcriptome states also occurred; these alterations were cell-autonomous, stable, and followed the phylogenetic tree of each cancer. There were marked differences in responses to anticancer drugs between even closely related cells of the same tumour. The results indicate that colorectal cancer cells experience substantial increases in somatic mutation rate compared to normal colorectal cells, and that genetic diversification of each cancer is accompanied by pervasive, stable and inherited differences in the biological states of individual cancer cells.
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http://dx.doi.org/10.1038/s41586-018-0024-3DOI Listing
April 2018

Recurrent histone mutations in T-cell acute lymphoblastic leukaemia.

Br J Haematol 2019 02 30;184(4):676-679. Epub 2018 Mar 30.

Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton, Cambridgeshire, UK.

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http://dx.doi.org/10.1111/bjh.15155DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6766952PMC
February 2019

The driver landscape of sporadic chordoma.

Nat Commun 2017 10 12;8(1):890. Epub 2017 Oct 12.

Cancer Genome Project, Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton, Cambridgeshire, CB10 1SA, UK.

Chordoma is a malignant, often incurable bone tumour showing notochordal differentiation. Here, we defined the somatic driver landscape of 104 cases of sporadic chordoma. We reveal somatic duplications of the notochordal transcription factor brachyury (T) in up to 27% of cases. These variants recapitulate the rearrangement architecture of the pathogenic germline duplications of T that underlie familial chordoma. In addition, we find potentially clinically actionable PI3K signalling mutations in 16% of cases. Intriguingly, one of the most frequently altered genes, mutated exclusively by inactivating mutation, was LYST (10%), which may represent a novel cancer gene in chordoma.Chordoma is a rare often incurable malignant bone tumour. Here, the authors investigate driver mutations of sporadic chordoma in 104 cases, revealing duplications in notochordal transcription factor brachyury (T), PI3K signalling mutations, and mutations in LYST, a potential novel cancer gene in chordoma.
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http://dx.doi.org/10.1038/s41467-017-01026-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5638846PMC
October 2017

Recurrent mutation of IGF signalling genes and distinct patterns of genomic rearrangement in osteosarcoma.

Nat Commun 2017 06 23;8:15936. Epub 2017 Jun 23.

Cancer Genome Project, Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton, Cambridgeshire CB10 1SA, UK.

Osteosarcoma is a primary malignancy of bone that affects children and adults. Here, we present the largest sequencing study of osteosarcoma to date, comprising 112 childhood and adult tumours encompassing all major histological subtypes. A key finding of our study is the identification of mutations in insulin-like growth factor (IGF) signalling genes in 8/112 (7%) of cases. We validate this observation using fluorescence in situ hybridization (FISH) in an additional 87 osteosarcomas, with IGF1 receptor (IGF1R) amplification observed in 14% of tumours. These findings may inform patient selection in future trials of IGF1R inhibitors in osteosarcoma. Analysing patterns of mutation, we identify distinct rearrangement profiles including a process characterized by chromothripsis and amplification. This process operates recurrently at discrete genomic regions and generates driver mutations. It may represent an age-independent mutational mechanism that contributes to the development of osteosarcoma in children and adults alike.
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http://dx.doi.org/10.1038/ncomms15936DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5490007PMC
June 2017

The interplay of long non-coding RNAs and MYC in cancer.

AIMS Biophys 2015;2(4):794-809. Epub 2015 Dec 1.

Department of Biochemistry, University of California, Riverside, CA 92521, USA.

Long non-coding RNAs (lncRNAs) are a class of RNA molecules that are changing how researchers view eukaryotic gene regulation. Once considered to be non-functional products of low-level aberrant transcription from non-coding regions of the genome, lncRNAs are now viewed as important epigenetic regulators and several lncRNAs have now been demonstrated to be critical players in the development and/or maintenance of cancer. Similarly, the emerging variety of interactions between lncRNAs and MYC, a well-known oncogenic transcription factor linked to most types of cancer, have caught the attention of many biomedical researchers. Investigations exploring the dynamic interactions between lncRNAs and MYC, referred to as the lncRNA-MYC network, have proven to be especially complex. Genome-wide studies have shown that MYC transcriptionally regulates many lncRNA genes. Conversely, recent reports identified lncRNAs that regulate MYC expression both at the transcriptional and post-transcriptional levels. These findings are of particular interest because they suggest roles of lncRNAs as regulators of MYC oncogenic functions and the possibility that targeting lncRNAs could represent a novel avenue to cancer treatment. Here, we briefly review the current understanding of how lncRNAs regulate chromatin structure and gene transcription, and then focus on the new developments in the emerging field exploring the lncRNA-MYC network in cancer.
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http://dx.doi.org/10.3934/biophy.2015.4.794DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4827443PMC
December 2015

In vivo caprine model for osteomyelitis and evaluation of biofilm-resistant intramedullary nails.

Biomed Res Int 2013 11;2013:674378. Epub 2013 Jun 11.

Department of Orthopaedic Surgery, Alpert Medical School, Brown University, Suite 200, 2 Dudley Street, Providence, RI 02905, USA.

Bone infection remains a formidable challenge to the medical field. The goal of the current study is to evaluate antibacterial coatings in vitro and to develop a large animal model to assess coated bone implants. A novel coating consisting of titanium oxide and siloxane polymer doped with silver was created by metal-organic methods. The coating was tested in vitro using rapid screening techniques to determine compositions which inhibited Staphylococcus aureus growth, while not affecting osteoblast viability. The coating was then applied to intramedullary nails and evaluated in vivo in a caprine model. In this pilot study, a fracture was created in the tibia of the goat, and Staphylococcus aureus was inoculated directly into the bone canal. The fractures were fixed by either coated (treated) or non-coated intramedullary nails (control) for 5 weeks. Clinical observations as well as microbiology, mechanical, radiology, and histology testing were used to compare the animals. The treated goat was able to walk using all four limbs after 5 weeks, while the control was unwilling to bear weight on the fixed leg. These results suggest the antimicrobial potential of the hybrid coating and the feasibility of the goat model for antimicrobial coated intramedullary implant evaluation.
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http://dx.doi.org/10.1155/2013/674378DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3693125PMC
December 2013

Niobium oxide-polydimethylsiloxane hybrid composite coatings for tuning primary fibroblast functions.

J Biomed Mater Res A 2014 May 24;102(5):1478-85. Epub 2013 Jun 24.

Alpert Medical School, Brown University, Providence, Rhode Island, 02903.

This study evaluates the potential of niobium oxide-polydimethylsiloxane (PDMS) composites for tuning cellular response of fibroblasts, a key cell type of soft tissue/implant interfaces. In this study, various hybrid coatings of niobium oxide and PDMS with different niobium oxide concentrations were synthesized and characterized using scanning electron microscopy, X-ray photoelectron spectrometry (XPS), and contact angle goniometry. The coatings were then applied to 96-well plates, on which primary fibroblasts were seeded. Fibroblast viability, proliferation, and morphology were assessed after 1, 2, and 3 days of incubation using WST-1 and calcein AM assays along with fluorescent microscopy. The results showed that the prepared coatings had distinct surface features with submicron spherical composites covered in a polymeric layer. The water contact angle measurement demonstrated that the hybrid surfaces were much more hydrophobic than the original pure niobium oxide and PDMS. The combination of surface roughness and chemistry resulted in a biphasic cellular response with maximum fibroblast density on substrate with 40 wt % of niobium oxide. The results of the current study indicate that by adjusting the concentration of niobium oxide in the coating, a desirable cell response can be achieved to improve tissue/implant interfaces.
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http://dx.doi.org/10.1002/jbm.a.34832DOI Listing
May 2014

Predicting pulmonary embolus in orthopedic trauma patients using the Wells score.

Orthopedics 2013 May;36(5):e642-7

Division of Orthopaedic Trauma, Department of Orthopaedics, Warren Alpert Medical School, Brown University, 593 Eddy St, Providence, RI 02903, USA.

The decision to perform computed tomography pulmonary angiography (CTPA) to rule out pulmonary embolism (PE) in orthopedic trauma patients is challenging. The Wells score is a commonly used clinical probability tool developed to determine the likelihood of PE and assist in determining the need for CTPA examination. This study evaluated the usefulness of the Wells score for predicting PE in patients admitted to the orthopedic trauma service. All patients who were admitted to the orthopedic trauma service at the authors' institution between 2001 and 2011 who underwent CTPA were identified. The Wells score was calculated retrospectively for each patient, and risk categories using the traditional and alternative interpretations of the Wells score were assigned. Pulmonary embolism was diagnosed in 27 (16%) of 169 patients who underwent CTPA. In total, 27 (0.39%) of 6854 patients admitted to the orthopedic trauma service were diagnosed with PE during initial hospitalization. Mean Wells score was 3.31 (95% confidence interval, ±.28) for the entire population, 3.32 for those without PE (95% confidence interval, ±.31), and 3.28 for those with PE (95% confidence interval, ±.72) (P=.91). Average times from admission to CTPA examination for those with and without PE were 6.18 and 5.7 days, respectively (P=.94). No significant correlation existed between the Wells score and CTPA results, indicating that the Wells score is limited in predicting PE risk in orthopedic trauma patients.
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http://dx.doi.org/10.3928/01477447-20130426-29DOI Listing
May 2013

Survey of high school students' perceptions about their iPod use, knowledge of hearing health, and need for education.

Lang Speech Hear Serv Sch 2012 Jan 15;43(1):14-35. Epub 2011 Aug 15.

University of California, Santa Barbara, USA.

Purpose: High school students' knowledge about hearing health and their perceptions of how they use personal listening devices (PLDs) including iPods were surveyed to determine the need, content, and preferred format for educational outreach to them.

Method: This study was a descriptive convenience survey of students at a California high school. An 83-item questionnaire was administered in December 2009 to assess students' demographics, knowledge of hearing health, perceived iPod use, and risk activities.

Results: The response rate was 56%. Most of the students perceived that they used iPods safely. However, responses indicated that many of the respondents could be at risk of injury to themselves or others if they became unaware of their surroundings while listening to iPods. Some students were knowledgeable about hearing health and safe iPod use, but most needed information about hearing loss and hearing conservation.

Conclusion: Most of the students needed education (e.g., via health classes or the Internet) about hearing health, the warning signs of hearing loss, and how to prevent hearing loss. Resources for educational audiologists are provided.
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http://dx.doi.org/10.1044/0161-1461(2011/10-0088)DOI Listing
January 2012

ChIP-seq analysis reveals distinct H3K27me3 profiles that correlate with transcriptional activity.

Nucleic Acids Res 2011 Sep 7;39(17):7415-27. Epub 2011 Jun 7.

Walter and Eliza Hall Institute, 1G Royal Parade, Parkville 3052, Australia.

Transcriptional control is dependent on a vast network of epigenetic modifications. One epigenetic mark of particular interest is tri-methylation of lysine 27 on histone H3 (H3K27me3), which is catalysed and maintained by Polycomb Repressive Complex 2 (PRC2). Although this histone mark is studied widely, the precise relationship between its local pattern of enrichment and regulation of gene expression is currently unclear. We have used ChIP-seq to generate genome-wide maps of H3K27me3 enrichment, and have identified three enrichment profiles with distinct regulatory consequences. First, a broad domain of H3K27me3 enrichment across the body of genes corresponds to the canonical view of H3K27me3 as inhibitory to transcription. Second, a peak of enrichment around the transcription start site (TSS) is commonly associated with 'bivalent' genes, where H3K4me3 also marks the TSS. Finally and most surprisingly, we identified an enrichment profile with a peak in the promoter of genes that is associated with active transcription. Genes with each of these three profiles were found in different proportions in each of the cell types studied. The data analysis techniques developed here will be useful for the identification of common enrichment profiles for other histone modifications that have important consequences for transcriptional regulation.
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http://dx.doi.org/10.1093/nar/gkr416DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3177187PMC
September 2011

From RNA-seq reads to differential expression results.

Genome Biol 2010 22;11(12):220. Epub 2010 Dec 22.

Bioinformatics Division, Walter and Eliza Hall Institute, 1G Royal Parade, Parkville 3052, Australia.

Many methods and tools are available for preprocessing high-throughput RNA sequencing data and detecting differential expression.
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http://dx.doi.org/10.1186/gb-2010-11-12-220DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3046478PMC
June 2011

Gene ontology analysis for RNA-seq: accounting for selection bias.

Genome Biol 2010 4;11(2):R14. Epub 2010 Feb 4.

Bioinformatics Division, The Walter and Eliza Hall Institute of Medical Research, 1G Royal Parade, Parkville 3052, Australia.

We present GOseq, an application for performing Gene Ontology (GO) analysis on RNA-seq data. GO analysis is widely used to reduce complexity and highlight biological processes in genome-wide expression studies, but standard methods give biased results on RNA-seq data due to over-detection of differential expression for long and highly expressed transcripts. Application of GOseq to a prostate cancer data set shows that GOseq dramatically changes the results, highlighting categories more consistent with the known biology.
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http://dx.doi.org/10.1186/gb-2010-11-2-r14DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2872874PMC
August 2010

Health literacy among Spanish-speaking patients in the emergency department.

J Natl Med Assoc 2008 Nov;100(11):1326-32

Department of Emergency Medicine, University of North Carolina, Chapel Hill, NC 27599, USA.

Study Objective: Health literacy influences a patient's ability to read and understand labels on medicine containers, appointment slips, informed-consent documents and medical instructions--all of which are considered basic health documents that a patient encounters in healthcare settings. Previous research suggests Spanish-speaking patients have low levels of health literacy. This study compares the functional health literacy (FHL) of Spanish- and English-speaking adult patients in a suburban emergency department (ED).

Methods: Through a prospective, matched cohort design, Spanish-speaking adult patients and pediatric guardians presenting to the ED were matched with English-speaking patients by age, gender and treatment area. Demographic information, including total years of school completed and self-assessed reading ability, was collected. The Test of Functional Health Literacy in Adults (TOFHLA) was administered in the subject's primary language. A score of <60 indicated inadequate FHL, 60-74 marginally adequate FHL, and >74 adequate literacy.

Results: Eighty-six matched pairs were enrolled. The median age was 30.5 years, and 56% were male. Spanish speakers averaged a TOFHLA score of 59.72, and English speakers 90.78. Only 7% of English speakers had less-than-adequate FHL compared to 74% of Spanish speakers. The average years of school completed were 10.59 (7.95 Spanish; 13.19 English), and 55% of English speakers reported "excellent" reading ability compared to 13% of Spanish speakers. Last grade completed (p=0.004) and self-assessed reading ability (p=0.0007) are predictors of TOFHLA scores. Those subjects who completed less than the eighth grade had inadequate FHL.

Conclusions: The majority of Spanish-speaking subjects have less-than-adequate FHL. Self-reported reading ability and years of school completed appear to predict FHL and may be clinically useful. Due to the disproportionately low level of health literacy among Spanish-speaking patients demonstrated in this and previous studies, future efforts should focus on developing programs that improve health literacy by providing this population with oral translations and pictorial and video instructions.
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http://dx.doi.org/10.1016/s0027-9684(15)31512-1DOI Listing
November 2008

Forced versus minimal intravenous hydration in the management of acute renal colic: a randomized trial.

J Endourol 2006 Oct;20(10):713-6

Comprehensive Kidney Stone Center, Duke University Medical Center, Durham, North Carolina, USA.

Background And Purpose: The management of acute renal colic is a problem commonly encountered by both urologists and emergency medicine physicians. The classic approach to managing uncomplicated acute renal colic involves hydration, along with imaging and pain control. Previous studies have suggested that hydration has a significant impact on patient comfort, as well as spontaneous stone passage. This study evaluated the effects of maintenance v forced hydration and its effect on the pain experienced from renal colic.

Patients And Methods: Forty male and 18 female patients with a mean age of 41 years suspected to have acute renal colic were identified in the emergency department. After screening and informed consent, the patients were enrolled in the study, and 43 patients were eventually available for analysis. Patients received intravenous (IV) analgesia, imaging with a noncontrast CT scan of abdomen and pelvis, and assignment to either forced IV hydration with 2 L of normal saline over 2 hours (N = 20) or minimal IV hydration at 20 mL of normal saline per hour (N = 23). A visual analog pain scale was completed hourly for a total of 4 hours. Demographic information, laboratory and imaging results, narcotic use in morphine equivalents (ME), and pain scores were recorded and compared. Spontaneous stone passage rates were also calculated by careful patient follow-up. Results were considered statistically significant at p < 0.05.

Results: Stone size was equivalent in the two treatment groups (p > 0.05). There was no difference in the narcotic requirement in ME (p = 0.644) between the two groups. Similarly, there was no difference in hourly pain score or stone-passage rates between the groups (p > 0.05).

Conclusions: Treatment of uncomplicated renal colic has traditionally included vigorous intravenous hydration, as well as medications for the control of pain and nausea. Our data suggest that maintenance intravenous fluids are as efficacious as forced hydration with regard to patient pain perception and narcotic use. Moreover, it appears the state of hydration has little impact on stone passage.
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http://dx.doi.org/10.1089/end.2006.20.713DOI Listing
October 2006

Renal cryoablation and radio frequency ablation: an evaluation of worst case scenarios in a porcine model.

J Urol 2005 Jun;173(6):2160-5

Division of Urology, Duke University Medical Center, Durham, North Carolina, USA.

Purpose: Although ablative technologies, including radio frequency (RF) ablation (RFA) and cryoablation (CA), are being used to treat renal masses, complications associated with injury to vital renal structures are not well understood. We investigated these worst case scenarios by deliberately targeting vital renal structures with CA or RFA in a porcine model.

Materials And Methods: Following surgical exposure of the right kidney in female pigs a cryoneedle or an RF probe was deliberately placed under visual and ultrasound guidance in the renal pelvis (CA in 5 pigs and RFA in 7), major calix (CA and RFA in 5 each) or subsegmental renal vessels (CA in 5 pigs and RFA in 7). Cryo-energy or RF energy was then applied to create a 3 cm lesion. After 10 days the kidneys underwent gross and histological examination for urine and blood extravasation, cell death and injury. Ex vivo retrograde pyelography was performed to evaluate for urinary fistulas.

Results: All pigs tolerated the treatment and no procedure related deaths occurred. No significant bleeding was noted. RFA and CA created reproducible lesions and areas of cell death and necrosis. Despite significant intentional injury to the collecting system no urinary fistulas were demonstrated in CA specimens (0 of 15). In contrast, damage to the renal pelvis (4 of 7) by dry (3 of 4) or wet (1 of 3) RFA was associated with a high likelihood of urinary extravasation.

Conclusions: This short-term study demonstrates that CA is safe, effective and not associated with urinary extravasation. In contrast, RFA to the renal pelvis is associated with urinary extravasation. Further studies are needed to support these findings.
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http://dx.doi.org/10.1097/01.ju.0000158125.80981.f1DOI Listing
June 2005

Ethnic background has minimal impact on the etiology of nephrolithiasis.

J Urol 2005 Jun;173(6):2001-4

Comprehensive Kidney Stone Center, Division of Urology, Department of Surgery, Duke University Medical Center, Durham, North Carolina, USA.

Purpose: Nephrolithiasis disproportionately affects white patients. However, recent studies propose an increase in the incidence of stone disease in nonwhite populations. We compared the metabolic risk factors of ethnically disparate stone formers from the same geographic region.

Materials And Methods: A retrospective review of 1,141 patients identified 98 (9%) nonwhite stone formers. Of these individuals 60 underwent a comprehensive metabolic evaluation, comprising 44 black, 8 Asian and 8 Hispanic patients. A similar sex and age matched group of 66 white stone forming patients were also identified for comparative analysis. Stone analyses were recorded when available. Urinary metabolic abnormalities were defined as low urine volume-urine volume less than 2,000 cc, gouty diathesis-pH 5.5 or less (normal level 5.5 to 6.5), hypercalciuria-calcium greater than 200 mg, hyperoxaluria-oxalate greater than 45 mg, hyperuricosuria-uric acid greater than 600 mg, hypocitraturia-citrate less than 600 mg and purine gluttony-sulfate greater than 20 mg.

Results: The incidence of metabolic abnormalities was surprisingly similar between the white and nonwhite stone formers. Whites have a higher prevalence of hypercalciuria compared with nonwhites (67% vs 25%, respectively, p <0.01). This comparison persisted when the white group was compared with individual ethnic groups (25% in each group). Whites also displayed a higher mean urinary calcium level (233 mg) than their nonwhite counterparts overall (146 mg), specifically with respect to blacks (146 mg, p <0.01). Asians had higher urine volumes with respect to whites and blacks (p <0.01) and, therefore, a decreased prevalence of low urine volumes (37.5% vs 74.2% and 79.5%, respectively). Hypocitraturia, hyperuricosuria, hyperoxaluria, gouty diathesis and high sulfate levels were equally represented among all ethnic groups.

Conclusions: Although there appears to be a predominance of stone disease among whites, all racial groups demonstrated a remarkable similarity in the incidence of underlying metabolic abnormalities. These results suggest that dietary and environmental factors may be as important as ethnicity in the etiology of stone disease.
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http://dx.doi.org/10.1097/01.ju.0000159076.70638.1eDOI Listing
June 2005

Lymphangioleiomyomatosis presenting as bladder outlet obstruction.

Urology 2005 Mar;65(3):589-90

Comprehensive Kidney Stone Center, Division of Urology, Department of Surgery, Duke University Medical Center, Durham, North Carolina 27710, USA.

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http://dx.doi.org/10.1016/j.urology.2004.11.039DOI Listing
March 2005