326,028 research outputs found
Estrogen receptor co-regulators as prognostic and predictive markers of endocrine therapy in early breast cancer: the role of SMRT and p160 family
No full textBackground: The estrogen receptor (ER) signaling pathway is the dominant driver of cell proliferation and survival in the majority of human breast cancers. Not surprisingly, endocrine treatment, such as the anti-estrogen tamoxifen, represents the most effective and widely used therapy for ER positive breast cancer patients. Unfortunately not all patients respond to endocrine treatment and a wide proportion of patients ultimately develop resistance and die. Selecting patients with an increased risk of recurrence and identifying those that might benefit from a particular therapy is of great value in order to personalize breast cancer therapies. A minority of breast cancers does not express ER and displays features of aggressiveness and poor prognosis. Prognostic markers are urgently needed for this subset of patients as well. The p160 family of ER co-activator is composed of three different members: SRC1, SRC2 and AIB1. SRC1 and AIB1 are frequently overexpressed in breast cancer and appear to be linked to hormone resistance, particularly in HER2 positive breast cancer. SMRT is an ER co-repressor that has been implicated in tamoxifen resistance. Data on p160 family members and SMRT expression in human breast cancer samples and its prognostic and predictive significance in endocrine treated patients are controversial or lacking altogether. Moreover, the role of these co-regulators in ER negative disease is poorly understood.
Methods: SRC1, SRC2, AIB1 and SMRT expression was determined by immunohistochemistry on tissue microarrays derived from two fully documented cohorts of 1812 and 1424 patients.
Results: HER2 and AIB1 dual-positive tumors were associated with markedly worse outcome compared to tumors overexpressing either HER2 or AIB1 alone, irrespective of ER status. In ER negative disease both SRC1 and AIB1 were linked to early relapse and death. Additionally, we found that co-expression of two or more SRCs were significantly associated with worse outcome in ER positive endocrine-treated patients. However, expression of any SRC alone was not a significant predictor of resistance to endocrine therapy. Low nuclear SMRT expression was associated with a significantly better outcome in untreated patients but not in tamoxifen-treated patients.
Conclusions: The SRC family of ER co-activators and nuclear SMRT are markers of early relapse in both ER negative and ER positive breast cancer. Evaluation of multiple markers co-expression (i.e. AIB1/HER2, multiple SRCs) rather than single markers allows a better assessment of breast cancer prognosis
The ansamycin antibiotic, rifamycin SV, inhibits BCL6 transcriptional repression and forms a complex with the BCL6-BTB/POZ domain
No full textBCL6 is a transcriptional repressor that is over-expressed due to chromosomal translocations, or other abnormalities, in ~40% of diffuse large B-cell lymphoma. BCL6 interacts with co-repressor, SMRT, and this is essential for its role in lymphomas. Peptide or small molecule inhibitors, which prevent the association of SMRT with BCL6, inhibit transcriptional repression and cause apoptosis of lymphoma cells in vitro and in vivo. In order to discover compounds, which have the potential to be developed into BCL6 inhibitors, we screened a natural product library. The ansamycin antibiotic, rifamycin SV, inhibited BCL6 transcriptional repression and NMR spectroscopy confirmed a direct interaction between rifamycin SV and BCL6. To further determine the characteristics of compounds binding to BCL6-POZ we analyzed four other members of this family and showed that rifabutin, bound most strongly. An X-ray crystal structure of the rifabutin-BCL6 complex revealed that rifabutin occupies a partly non-polar pocket making interactions with tyrosine58, asparagine21 and arginine24 of the BCL6-POZ domain. Importantly these residues are also important for the interaction of BLC6 with SMRT. This work demonstrates a unique approach to developing a structure activity relationship for a compound that will form the basis of a therapeutically useful BCL6 inhibitor
Public relations in Singapore: The Love-Hate relationship with social media
No full textThe growth of social media has undoubtedly impacted upon public relations practice even in non-liberal societies. In December 2011, operators of Singapore 19s metro train system, the Singapore Mass Rapid Transit (SMRT) Corporation, suffered a reputational crisis that led to the eventual resignation of its Chief Executive Officer as a result of social media. A series of logistic faults were reported on social media platforms by affected commuters through the use of mobile media technologies as the situations unfolded. This case is pivotal, as one of several in Singapore 19s recent history that has conclusively indicated a strategic and professional value to social media in public relations in a society typically known for its restrictive, non-liberal stance.
This dissertation is a multidisciplinary investigation that relates to Grunig and Hunt 19s oft-unattainable, two-way symmetrical communication model. The impact of new media technologies will be analysed through crisis communication, a facet of public relations where social media can potentially be the most influential driving force.
Acknowledging that existing data is not substantial enough to accurately support this thesis, it employs a qualitative research design backed by practitioner interviews in order to extract relevant and insightful accounts of industry perceptions regarding the practical utilisation of social media tools amongst professionals. As a result, this study represents the ongoing changes and evolutions being made to public relations as social media continues to evolve.
In this thesis, I propose that social media has influenced the scope of public relations and organisational frameworks currently in Singapore, giving rise to a generation of empowered audiences, who need to be treated with far more caution and respect than ever before. Within this, I also highlight how the rise of the digital era has actually resulted in increased attention to the field of public relations. The SMRT crisis will be used as a key case study to illustrate the ongoing changes. The ultimate aim of this thesis is to examine how social media has impacted on public relations and crisis communication in an authoritarian context
Dvojí smrt v Benátkách: srovnání literární předlohy Thomase Manna s její filmovou adaptací Luchina Viscontiho
No full textPráce srovnává novelu T. Manna "Smrt v Benátkách" s její stejnojmennou filmovou adaptací Luchina Viscontiho.Dokončená práce s úspěšnou obhajobo
The Versatility of SMRT Sequencing
No full textThe adoption of single molecule real-time (SMRT) sequencing [1] is becoming widespread, not only in basic science, but also in more applied areas such as agricultural, environmental, and medical research. SMRT sequencing offers important advantages over current short-read DNA sequencing technologies, including exceptionally long read lengths (20 kb ormore), unparalleled consensus accuracy, and the ability to sequence native, non-amplified, DNA molecules. These sequencing characteristics enable creation of highly accurate de novo genome assemblies, characterization of complex structural variation, direct characterization of nucleotide base modifications, full-length RNA isoform sequencing, phasing of genetic variants, low frequency mutation detection, and clonal evolution determination [2,3]. This Special Issue of Genes is a collection of articles showcasing the latest developments and the breadth of applications enabled by SMRT sequencing technology. In basic science, SMRT sequencing enables studies into the molecular mechanisms of living cells at a new level of resolution. Perhaps the most advantageous feature of SMRT sequencing is that it facilitates sequencing of long DNA molecules at a very high accuracy. This has enabled the construction of high-quality reference genomes for a wide range of species, including new human genome assemblies, as presented in this special issue [4]. In addition, when SMRT sequencing is performed on native non-amplified DNA molecules, it is possible to access several layers of additional information hidden in the kinetic signals emitted by the polymerases during the sequencing reaction [1]. This kinetic information has been used to detect epigenetic modifications at base pair resolution and even phasing of methylation signatures in diploid organisms, as presented in this special issue [5]. Several important discoveries have already been made from this kinetic information, such as the widespread presence of 6mA modifications in the human genome [6], a modification that was previously thought to only be present in bacterial genomes. In addition to base modifications, SMRT sequencing data also enables us to study other events, such as DNA conformations [7]. Another aspect of SMRT sequencing is that it can be used to study RNA, and it is currently the only technology that can generate high-quality continuous sequences for full-length transcripts up to 10 kb or more. This makes it possible to study splicing variation at a completely new level of resolution [8,9]. SMRT sequencing is also paving the way for a new generation of computational approaches to explore and interpret these rich datasets [10–12]. In summary, SMRT sequencing is enhancing and even opening up new areas of basic research that were not accessible with previous sequencing technologies. In terms of more applied areas, agriculture is benefiting from the advent of SMRT sequencing for examining important microbes, plants, and animals. SMRT sequencing, often with complementary technologies, has produced new genome assemblies for important crops, such as apples, maize, wine grapes, coffee, rice, black raspberries, asparagus, and cotton [11,13–20]. SMRT transcriptome sequencing has also given new insights into gene structures for rice, wheat, maize, sorghum, barley, and cotton [18,21–25]. Besides providing new references, these projects will improve plant cultivation, Genes 2019, 10, 24; doi:10.3390/genes10010024 www.mdpi.com/journal/genes Genes 2019, 10, 24 2 of 5 such as identifying drought and disease resistant genes. Strategies to detect genetically modified organisms (GMOs) have also been proposed and enhanced with SMRT sequencing [26]. Animal genome assemblies have been produced for several agriculturally valuable species, such as the horse, cow, goat, chicken (including its transcriptome), and commercially important fish like haddock and cod [27–33]. These will lead to improvements in animal breeding, management, and disease resistance. Finally, sequencing of pathogenic bacteria and fungi affecting agriculturally important species is providing insight into the diversity and virulence factors of these pathogens, which in turn will assist in disease risk and management [34–36]. In environmental research, systematic efforts are ongoing to generate reference sequences for thousands of bacterial strains and microorganisms. Recently, this has expanded to the genomes of larger organisms, including vertebrates [37]. SMRT sequencing can also play an important role in ecology research, such as monitoring the composition of fungi in environmental soil or water samples [38,39]. New high-quality references for animal genomes, such as the great apes [40], will provide an invaluable resource for future evolutionary studies. During the last few years, new genome assemblies have also been created for several endangered species, including Hawaii’s last crow species [41], aiding in conservation efforts. Though SMRT sequencing has primarily been applied to basic research, there is a growing implementation for clinical utility [3,42]. The long and highly accurate reads produced from SMRT sequencing have proven to be useful to resolve complex and repetitive regions of the human genome associated with disease. SMRT sequencing is also a sensitive method to detect minor variants in cancer and infectious disease. Although most current methods are based on targeted sequencing, the value of long reads is also becoming apparent for whole-genome sequencing, which allows clinical professionals to resolve repeat expansions, transposable element insertions, and other complex genomic rearrangements that are difficult or even impossible to assess using short-read sequence data. As we look forward, this technology will provide even longer and more accurate reads at a higher throughput. This will enable routine de novo assembly of both alleles in large diploid genomes, accompanied with tissue specific epigenetic DNA modification information. As a consequence, there will be a demand for a new generation of computational tools to compare complete genomes to each other, as opposed to a reference standard, and to phase genetic variants and epigenetic modifications over large chromosomal regions. By sequencing thousands of individuals with long reads, it will be possible to obtain a detailed picture of complex structural variation within large population cohorts of humans, as well as for other species. Such endeavors will give new insights to the function of the repetitive parts of the genome, and likely explain the cause of many genomic diseases. Looking further on the horizon, SMRT sequencing can be envisioned in combination with other technical advances, such as single cell sequencing to provide information on the epigenetic modifications occurring in single cells. SMRT sequencing has been steadily evolving since the commercial introduction of the technology in 2011. Just as short-read technologies have replaced microarrays and Sanger sequencing for a host of applications, we envision long-read single-molecule sequencing to replace short-read platforms for a majority of applications, as well as continue to evolve into new applications, throughout many different areas in the coming decade
DNA methylation assessed by SMRT sequencing is linked to mutations in Neisseria meningitidis isolates
No full textThe Gram-negative bacterium Neisseria meningitidis features extensive genetic variability. To present, proposed virulence genotypes are also detected in isolates from asymptomatic carriers, indicating more complex mechanisms underlying variable colonization modes of N. meningitidis. We applied the Single Molecule, Real-Time (SMRT) sequencing method from Pacific Biosciences to assess the genome-wide DNA modification profiles of two genetically related N. meningitidis strains, both of serogroup A. The resulting DNA methylomes revealed clear divergences, represented by the detection of shared and of strain-specific DNA methylation target motifs. The positional distribution of these methylated target sites within the genomic sequences displayed clear biases, which suggest a functional role of DNA methylation related to the regulation of genes. DNA methylation in N. meningitidis has a likely underestimated potential for variability, as evidenced by a careful analysis of the ORF status of a panel of confirmed and predicted DNA methyltransferase genes in an extended collection of N. meningitidis strains of serogroup A. Based on high coverage short sequence reads, we find phase variability as a major contributor to the variability in DNA methylation. Taking into account the phase variable loci, the inferred functional status of DNA methyltransferase genes matched the observed methylation profiles. Towards an elucidation of presently incompletely characterized functional consequences of DNA methylation in N. meningitidis, we reveal a prominent colocalization of methylated bases with Single Nucleotide Polymorphisms (SNPs) detected within our genomic sequence collection. As a novel observation we report increased mutability also at 6mA methylated nucleotides, complementing mutational hotspots previously described at 5mC methylated nucleotides. These findings suggest a more diverse role of DNA methylation and Restriction-Modification (RM) systems in the evolution of prokaryotic genomes
In cortical neurons HDAC3 suppresses RD4-dependent SMRT export
No full textThe transcriptional corepressor SMRT controls neuronal responsiveness of several transcription factors and can regulate neuroprotective and neurogenic pathways. SMRT is a multi-domain protein that complexes with HDAC3 as well as being capable of interactions with HDACs 1, 4, 5 and 7. We previously showed that in rat cortical neurons, nuclear localisation of SMRT requires histone deacetylase activity: Inhibition of class I/II HDACs by treatment with trichostatin A (TSA) causes redistribution of SMRT to the cytoplasm, and potentiates the activation of SMRT-repressed nuclear receptors. Here we have sought to identify the HDAC(s) and region(s) of SMRT responsible for anchoring it in the nucleus under normal circumstances and for mediating nuclear export following HDAC inhibition. We show that in rat cortical neurons SMRT export can be triggered by treatment with the class I-preferring HDAC inhibitor valproate and the HDAC2/3-selective inhibitor apicidin, and by HDAC3 knockdown, implicating HDAC3 activity as being required to maintain SMRT in the nucleus. HDAC3 interaction with SMRT's deacetylation activation domain (DAD) is known to be important for activation of HDAC3 deacetylase function. Consistent with a role for HDAC3 activity in promoting SMRT nuclear localization, we found that inactivation of SMRT's DAD by deletion or point mutation triggered partial redistribution of SMRT to the cytoplasm. We also investigated whether other regions of SMRT were involved in mediating nuclear export following HDAC inhibition. TSA- and valproate-induced SMRT export was strongly impaired by deletion of its repression domain-4 (RD4). Furthermore, over-expression of a region of SMRT containing the RD4 region suppressed TSA-induced export of full-length SMRT. Collectively these data support a model whereby SMRT's RD4 region can recruit factors capable of mediating nuclear export of SMRT, but whose function and/or recruitment is suppressed by HDAC3 activity. Furthermore, they underline the fact that HDAC inhibitors can cause reorganization and redistribution of corepressor complexes
Sub-megabase resolution tiling (SMRT) array-based comparative genomic hybridization profiling reveals novel gains and losses of chromosomal regions in Hodgkin Lymphoma and Anaplastic Large Cell Lymphoma cell lines-2
No full text<p><b>Copyright information:</b></p><p>Taken from "Sub-megabase resolution tiling (SMRT) array-based comparative genomic hybridization profiling reveals novel gains and losses of chromosomal regions in Hodgkin Lymphoma and Anaplastic Large Cell Lymphoma cell lines"</p><p>http://www.molecular-cancer.com/content/7/1/2</p><p>Molecular Cancer 2008;7():2-2.</p><p>Published online 7 Jan 2008</p><p>PMCID:PMC2254646.</p><p></p
Sub-megabase resolution tiling (SMRT) array-based comparative genomic hybridization profiling reveals novel gains and losses of chromosomal regions in Hodgkin Lymphoma and Anaplastic Large Cell Lymphoma cell lines-3
No full text<p><b>Copyright information:</b></p><p>Taken from "Sub-megabase resolution tiling (SMRT) array-based comparative genomic hybridization profiling reveals novel gains and losses of chromosomal regions in Hodgkin Lymphoma and Anaplastic Large Cell Lymphoma cell lines"</p><p>http://www.molecular-cancer.com/content/7/1/2</p><p>Molecular Cancer 2008;7():2-2.</p><p>Published online 7 Jan 2008</p><p>PMCID:PMC2254646.</p><p></p>reen labeled FISH probes, respectively
Sub-megabase resolution tiling (SMRT) array-based comparative genomic hybridization profiling reveals novel gains and losses of chromosomal regions in Hodgkin Lymphoma and Anaplastic Large Cell Lymphoma cell lines-1
No full text<p><b>Copyright information:</b></p><p>Taken from "Sub-megabase resolution tiling (SMRT) array-based comparative genomic hybridization profiling reveals novel gains and losses of chromosomal regions in Hodgkin Lymphoma and Anaplastic Large Cell Lymphoma cell lines"</p><p>http://www.molecular-cancer.com/content/7/1/2</p><p>Molecular Cancer 2008;7():2-2.</p><p>Published online 7 Jan 2008</p><p>PMCID:PMC2254646.</p><p></p
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