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Search Results: 1 - 10 of 203693 matches for " Jeremy P Blaydes "
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Down-Regulation of DNA Mismatch Repair Enhances Initiation and Growth of Neuroblastoma and Brain Tumour Multicellular Spheroids
Samuel L. Collins, Rodolphe Hervé, C. W. Keevil, Jeremy P. Blaydes, Jeremy S. Webb
PLOS ONE , 2011, DOI: 10.1371/journal.pone.0028123
Abstract: Multicellular tumour spheroid (MCTS) cultures are excellent model systems for simulating the development and microenvironmental conditions of in vivo tumour growth. Many documented cell lines can generate differentiated MCTS when cultured in suspension or in a non-adhesive environment. While physiological and biochemical properties of MCTS have been extensively characterized, insight into the events and conditions responsible for initiation of these structures is lacking. MCTS are formed by only a small subpopulation of cells during surface-associated growth but the processes responsible for this differentiation are poorly understood and have not been previously studied experimentally. Analysis of gene expression within spheroids has provided clues but to date it is not known if the observed differences are a cause or consequence of MCTS growth. One mechanism linked to tumourigenesis in a number of cancers is genetic instability arising from impaired DNA mismatch repair (MMR). This study aimed to determine the role of MMR in MCTS initiation and development. Using surface-associated N2a and CHLA-02-ATRT culture systems we have investigated the impact of impaired MMR on MCTS growth. Analysis of the DNA MMR genes MLH1 and PMS2 revealed both to be significantly down-regulated at the mRNA level compared with non-spheroid-forming cells. By using small interfering RNA (siRNA) against these genes we show that silencing of MLH1 and PMS2 enhances both MCTS initiation and subsequent expansion. This effect was prolonged over several passages following siRNA transfection. Down-regulation of DNA MMR can contribute to tumour initiation and progression in N2a and CHLA-02-ATRT MCTS models. Studies of surface-associated MCTS differentiation may have broader applications in studying events in the initiation of cancer foci.
Role of the unique N-terminal domain of CtBP2 in determining the subcellular localisation of CtBP family proteins
Lee M Bergman, Laila Morris, Matthew Darley, Alexander H Mirnezami, Samal C Gunatilake, Jeremy P Blaydes
BMC Cell Biology , 2006, DOI: 10.1186/1471-2121-7-35
Abstract: Here we show that amino acids (a.a.) 4–14 of CtBP2 direct CtBP2 into an almost exclusively nuclear distribution in cell lines of diverse origins. Whilst this sequence contains similarity to known nuclear localisation motifs, it cannot drive nuclear localisation of a heterologous protein, but rather has been shown to function as a p300 acetyltransferase-dependent nuclear retention sequence. Here we define the region of CtBP2 required to co-operate with a.a. 4–14 to promote CtBP2 nuclear accumulation as being within a.a. 1–119. In addition, we show that a.a. 120–445 of CtBP2 can also promote CtBP2 nuclear accumulation, independently of a.a. 4–14. Finally, CtBP1 and CtBP2 can form heterodimers, and we show that the interaction with CtBP2 is one mechanism whereby CtBP1 can be recruited to the nucleus.Together, these findings represent key distinctions in the regulation of the functions of CtBP family members that may have important implications as to their roles in development, and cell differentiation and survival.CtBP proteins were originally identified as C-terminal binding proteins of type 2/5 adenovirus E1A proteins [1]. They function primarily in the nucleus as transcriptional co-repressors, modulating the activity of a large number of transcriptional repressors via recruitment of chromatin modifiers such as histone deacetylases, histone methyltransferases and polycomb proteins [2-4], and sequestration of histone acetyltransferases [5]. CtBP proteins also play a role in the cytoplasm in regulating mitotic Golgi membrane fissioning [6,7], and also associate with centrosomes during mitosis [8]. CtBP proteins have been implicated in tumorigenesis, as their interaction with the C-terminus of E1A is essential for immortalisation of primary rodent cells, and also negatively regulates E1A-mediated transformation, tumorigenicity and metastasis [1,9,10]. In addition, many transcriptional repressors regulated by CtBPs are involved in pathways associated with tumorigenesis,
Selective anticancer activity of a hexapeptide with sequence homology to a non-kinase domain of Cyclin Dependent Kinase 4
Hilmar M Warenius, Jeremy D Kilburn, Jon W Essex, Richard I Maurer, Jeremy P Blaydes, Usha Agarwala, Laurence A Seabra
Molecular Cancer , 2011, DOI: 10.1186/1476-4598-10-72
Abstract: A search for a potential functional site of non-kinase activity present in Cdk4 but not Cdk2 or Cdk6 revealed a previously-unidentified loop on the outside of the C'-terminal non-kinase domain of Cdk4, containing a central amino-acid sequence, Pro-Arg-Gly-Pro-Arg-Pro (PRGPRP). An isolated hexapeptide with this sequence and its cyclic amphiphilic congeners are selectively lethal at high doses to a wide range of human cancer cell lines whilst sparing normal diploid keratinocytes and fibroblasts. Treated cancer cells do not exhibit the wide variability of dose response typically seen with other anticancer agents. Cancer cell killing by PRGPRP, in a cyclic amphiphilic cassette, requires cells to be in cycle but does not perturb cell cycle distribution and is accompanied by altered relative Cdk4/Cdk1 expression and selective decrease in ATP levels. Morphological features of apoptosis are absent and cancer cell death does not appear to involve autophagy.These findings suggest a potential new paradigm for the development of broad-spectrum cancer specific therapeutics with a companion diagnostic biomarker and a putative functional site for kinase-unrelated activities of Cdk4.Cdk4 has been actively pursued, over the last two decades, as a promising anticancer drug target [1,2] based on its role in cell cycle control [3] and its widespread deregulation in a multiplicity of different tumours [4]. Single agent activity of cyclin dependent kinase inhibitors in general has, however, been disappointing, with low percentages of objective responses [5], and no Cdk inhibitor has yet been approved as an anticancer drug [6] In particular, the specific Cdk4 inhibitor, flavopiridol, yielded no objective responses in phase II studies of metastatic melanoma, endometrial adenocarcinoma and multiple myeloma [7] when used as a single agent. Following encouraging animal studies [8], newer Cdk4 kinase inhibitors such as PD 0332991, are now entering clinical trials in combination with agents of
Influence of the MDM2 single nucleotide polymorphism SNP309 on tumour development in BRCA1 mutation carriers
Ellen R Copson, Helen E White, Jeremy P Blaydes, David O Robinson, Peter W Johnson, Diana M Eccles
BMC Cancer , 2006, DOI: 10.1186/1471-2407-6-80
Abstract: Genomic DNA was obtained for 102 healthy controls and 116 patients with established pathogenic mutations of BRCA1 and Pyrosequencing technology? was used to determine the genotype at the MDM2 SNP309 locus.The polymorphism was present in 52.9% of the controls (G/T in 37.3% and G/G in 15.6%) and 58.6% of the BRCA1 mutation carriers (47.4% G/T and 11.2% G/G). Incidence of malignancy in female BRCA1 carriers was not significantly higher in SNP309 carriers than in wildtype (T/T) individuals (72.7% vs. 75.6%, p = 1.00). Mean age of diagnosis of first breast cancer was 41.2 years in the SNP309 G/G genotype carriers, 38.6 years in those with the SNP309 G/T genotype and 39.0 years in wildtype subjects (p = 0.80).We found no evidence that the MDM2 SNP309 accelerates tumour development in carriers of known pathogenic germline mutations of BRCA1.Inheritance of a truncating mutation of the breast cancer predisposition gene BRCA1 has been reported to carry a lifetime risk of breast cancer of between 50 and 80%, with age at onset of first malignancy varying from the 2nd to the 8th decade [1,2]. Clinical studies indicate that BRCA1 mutation carriers can benefit significantly from preventative surgery, with prophylactic oophorectomy reducing breast cancer rates by up to 60% and ovarian cancer rates by 95%, and prophylactic double mastectomy reducing the incidence of breast cancer by up to 90% [3,4]. These two interventions are however major surgical procedures with potentially significant psychological and medical sequelae. The ability to predict whether a BRCA1 mutation carrier is likely to develop malignant disease early or late in life would facilitate the clinical management of these patients.No differences in penetrance have yet been documented for different BRCA1 truncating mutations [2]. Inter-individual variation in the speed at which BRCA1 mutation carriers develop cancer is likely to be influenced by environmental factors, but may also be affected by co-inheritance of othe
The Effect of Wind Power Installations on Coastal Tourism
Meredith Blaydes Lilley,Jeremy Firestone,Willett Kempton
Energies , 2010, DOI: 10.3390/en3010001
Abstract: We surveyed more than 1,000 randomly sampled, out-of-state tourists at Delaware, USA beaches in 2007. After providing respondents with wind turbine project photo-simulations at several distances, we inquired about the effect development would have on visitation. Approximately one-quarter stated that they would switch beaches if an offshore wind project was located 10 km from the coast, with avoidance diminishing with greater distance from shore. Stated avoidance is less than: avoidance with a fossil fuel power plant located the same distance inland; attraction to a beach with offshore wind turbines; and the percentage stating they would likely pay to take a boat tour.
Loss of C-terminal binding protein transcriptional corepressor leads to aberrant mitosis and cell death in breast cancer cells
L Bergman, J Blaydes
Breast Cancer Research , 2006, DOI: 10.1186/bcr1556
Abstract: In this study, we have continued investigation into the role of CtBPs in breast cancer cell survival, identifying a previously unknown function for CtBPs in the regulation of the mitotic spindle checkpoint. Loss of CtBP expression by RNAi results in a marked decrease in cell number, and in reduced cell viability and clonogenicity. We find that this apparent cell death does not occur by a traditional caspase-mediated apoptotic pathway.Detailed microscopic analysis of the morphology of MCF7 breast cancer cells lacking CtBPs reveals an increase in the number of cells containing abnormal micronucleated cells and dividing cells with lagging chromosomes, indicative of aberrant mitotic chromosomal segregation. Live cell imaging reveals defects in cell abcission after mitosis following CtBP knockdown. Furthermore, cells lacking CtBP fail to undergo mitotic arrest induced by spindle toxins, indicating a spindle checkpoint defect. The loss of cell viability in breast cancer cells following CtBP inhibition is most probably a consequence of aberrant mitosis and cell death by mitotic catastrophe. Here we present a detailed characterization of the mechanism by which CtBPs are involved in mitosis and cell survival, which we hope will increase our understanding of how breast cancer cells evade cell death, and ultimately lead to new treatments for patients.This research was funded by Breast Cancer Campaign.
Low-Load Bench Press Training to Fatigue Results in Muscle Hypertrophy Similar to High-Load Bench Press Training  [PDF]
Riki Ogasawara, Jeremy P. Loenneke, Robert S. Thiebaud, Takashi Abe
International Journal of Clinical Medicine (IJCM) , 2013, DOI: 10.4236/ijcm.2013.42022

The purpose of this study was to determine whether the training responses observed with low-load resistance exercise to volitional fatigue translates into significant muscle hypertrophy, and compare that response to high-load resistance training. Nine previously untrained men (aged 25 [SD 3] years at the beginning of the study, standing height 1.73 [SD 0.07] m, body mass 68.9 [SD 8.1] kg) completed 6-week of high load-resistance training (HL-RT) (75% of one repeti-tion maximal [1RM], 3-sets, 3x/wk) followed by 12 months of detraining. Following this, subjects completed 6 weeks of low load-resistance training (LL-RT) to volitional fatigue (30% 1 RM, 4 sets, 3x/wk). Increases (p < 0.05) in magnetic resonance imaging-measured triceps brachii and pectorals major muscle cross-sectional areas were similar for both HL-RT (11.9% and 17.6%, respectively) and LL-RT (9.8% and 21.1%, respectively). In addition, both groups increased (p < 0.05) 1RM and maximal elbow extension strength following training; however, the percent increases in 1RM (8.6% vs. 21.0%) and elbow extension strength (6.5% vs. 13.9%) were significantly (p < 0.05) lower with LL-RT. Both protocols elicited similar increases in muscle cross-sectional area, however differences were observed in strength. An explanation of the smaller relative increases in strength may be due to the fact that detraining after HL-RT did not cause strength values to return to baseline levels thereby producing smaller changes in strength. In addition, the results may also suggest that the consistent practice of lifting a heavy load is necessary to maximize gains in muscular strength of the trained movement. These results demonstrate that significant muscle hypertrophy can occur without high-load resistance training and suggests that the focus on percentage of external load as the important deciding factor on muscle hypertrophy is too simplistic and

Blockade of Pachytene piRNA Biogenesis Reveals a Novel Requirement for Maintaining Post-Meiotic Germline Genome Integrity
Ke Zheng,P. Jeremy Wang
PLOS Genetics , 2012, DOI: 10.1371/journal.pgen.1003038
Abstract: Piwi-interacting RNAs are a diverse class of small non-coding RNAs implicated in the silencing of transposable elements and the safeguarding of genome integrity. In mammals, male germ cells express two genetically and developmentally distinct populations of piRNAs at the pre-pachytene and pachytene stages of meiosis, respectively. Pre-pachytene piRNAs are mostly derived from retrotransposons and required for their silencing. In contrast, pachytene piRNAs originate from ~3,000 genomic clusters, and their biogenesis and function remain enigmatic. Here, we report that conditional inactivation of the putative RNA helicase MOV10L1 in mouse spermatocytes produces a specific loss of pachytene piRNAs, significant accumulation of pachytene piRNA precursor transcripts, and unusual polar conglomeration of Piwi proteins with mitochondria. Pachytene piRNA–deficient spermatocytes progress through meiosis without derepression of LINE1 retrotransposons, but become arrested at the post-meiotic round spermatid stage with massive DNA damage. Our results demonstrate that MOV10L1 acts upstream of Piwi proteins in the primary processing of pachytene piRNAs and suggest that, distinct from pre-pachytene piRNAs, pachytene piRNAs fulfill a unique function in maintaining post-meiotic genome integrity.
Changing Patterns of Dengue Epidemiology and Implications for Clinical Management and Vaccines
Cameron P. Simmons ,Jeremy Farrar
PLOS Medicine , 2009, DOI: 10.1371/journal.pmed.1000129
Expectation-Maximization Gaussian-Mixture Approximate Message Passing
Jeremy P. Vila,Philip Schniter
Mathematics , 2012, DOI: 10.1109/TSP.2013.2272287
Abstract: When recovering a sparse signal from noisy compressive linear measurements, the distribution of the signal's non-zero coefficients can have a profound effect on recovery mean-squared error (MSE). If this distribution was apriori known, then one could use computationally efficient approximate message passing (AMP) techniques for nearly minimum MSE (MMSE) recovery. In practice, though, the distribution is unknown, motivating the use of robust algorithms like LASSO---which is nearly minimax optimal---at the cost of significantly larger MSE for non-least-favorable distributions. As an alternative, we propose an empirical-Bayesian technique that simultaneously learns the signal distribution while MMSE-recovering the signal---according to the learned distribution---using AMP. In particular, we model the non-zero distribution as a Gaussian mixture, and learn its parameters through expectation maximization, using AMP to implement the expectation step. Numerical experiments on a wide range of signal classes confirm the state-of-the-art performance of our approach, in both reconstruction error and runtime, in the high-dimensional regime, for most (but not all) sensing operators.
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