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Search Results: 1 - 10 of 146015 matches for " Spencer B. Gibson "
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Targeting Metabolism and Autophagy in the Context of Haematologic Malignancies
Versha Banerji,Spencer B. Gibson
International Journal of Cell Biology , 2012, DOI: 10.1155/2012/595976
Abstract: Autophagy is a cellular process that maintains the homeostasis of the normal cell. It not only allows for cell survival in times of metabolic stress with nutrient recycling but also is able to lead to cell death when required. During malignant transformation the cell is able to proliferate and survive. This is due to altered cell metabolism and the presence of altered genetic changes that maintain the cell survival. Metabolism was considered an innocent bystander that was a consequence of the increased nutrient requirement for the survival and proliferation of haematological malignancies. The interdependency of metabolism and cellular mechanisms such as autophagy are becoming more evident and important. This interdependence contributes to increased cancer progression and drug resistance. In this paper we aim to discuss autophagy, how it pertains to metabolism in the context of hematologic malignancies, and the implications for therapy. 1. Introduction Autophagy was first described in the 1960s but its importance in various physiological conditions in addition to the basic molecular understanding of autophagy has only come into focus in the last decade. The word autophagy is derived from Greek: auto, meaning “self” and phagy, “to eat.” This term was coined due to the process by which cellular components are degraded through the lysosomal enzymatic pathway providing a cell with essential amino acids, nucleotides, and fatty acids that enable production of the elements required for energy and macromolecule production [1, 2]. Normal cells engage in autophagy as a means to survive disruptions in nutrient and growth factor availability. It also serves to eliminate damaged organelles and proteins to prevent accumulation. This prevents them from becoming toxic to the cell. If autophagy is prolonged to a point where normal cell function is compromised, cells undergo cell death either through apoptosis or by autophagy itself. One of the main inducers of autophagy is metabolic stress, and understanding the relationship between autophagy and metabolism could lead to better therapeutic strategies in treatment of haematological malignancies. 2. Regulation of Autophagy Autophagy is characterized by cytoplasmic constituents sequestered into double-membraned vacuoles called autophagosomes. Autophagosomes then fuse with lysosomes (autolysosomes). Autolysosomes degrade cellular components releasing required nutrients to the cell. The regulation of autophagosome and autolysosome structures requires both positive and negative signaling pathways. The discovery in yeast of
Cucurbitacin-I (JSI-124) activates the JNK/c-Jun signaling pathway independent of apoptosis and cell cycle arrest in B Leukemic Cells
Ganchimeg Ishdorj, James B Johnston, Spencer B Gibson
BMC Cancer , 2011, DOI: 10.1186/1471-2407-11-268
Abstract: BJAB, I-83, NALM-6 and primary CLL cells were treated with JSI-124 as indicated. Apoptosis was measured using flow cytometry for accumulation of sub-G1 phase cells (indicator of apoptosis) and Annexin V/PI staining. Cell cycle was analyzed by FACS for DNA content of G1 and G2 phases. Changes in phosphorylation and protein expression of p38, Erk1/2, JNK, c-Jun, and XIAP were detected by Western blot analysis. STAT3 and c-Jun genes were knocked out using siRNA transfection. VEGF expression was determined by mRNA and protein levels by RT-PCR and western blotting. Streptavidin Pull-Down Assay was used to determine c-Jun binding to the AP-1 DNA binding site.Herein, we show that JSI-124 activates c-Jun N-terminal kinase (JNK) and increases both the expression and serine phosphorylation of c-Jun protein in the B leukemic cell lines BJAB, I-83 and NALM-6. JSI-124 also activated MAPK p38 and MAPK Erk1/2 albeit at lower levels than JNK activation. Inhibition of the JNK signaling pathway failed to effect cell cycle arrest or apoptosis induced by JSI-124 but repressed JSI-124 induced c-Jun expression in these leukemia cells. The JNK pathway activation c-Jun leads to transcriptional activation of many genes. Treatment of BJAB, I-83, and NALM-6 cells with JSI-124 lead to an increase of Vascular Endothelial Growth Factor (VEGF) at both the mRNA and protein level. Knockdown of c-Jun expression and inhibition of JNK activation significantly blocked JSI-124 induced VEGF expression. Pretreatment with recombinant VEGF reduced JSI-124 induced apoptosis.Taken together, our data demonstrates that JSI-124 activates the JNK signaling pathway independent of apoptosis and cell cycle arrest, leading to increased VEGF expression.Cucurbitacin-I (JSI-124) can be found in a variety of plants that have been used for centuries as folk medicines in Asia [1-3]. However, the molecular mechanisms responsible for the various biological effects of JSI-124 have not been fully investigated. JSI-124 is a sel
Estrogen Regulation of Anti-Apoptotic Bcl-2 Family Member Mcl-1 Expression in Breast Cancer Cells
Jennifer L. Schacter, Elizabeth S. Henson, Spencer B. Gibson
PLOS ONE , 2014, DOI: 10.1371/journal.pone.0100364
Abstract: Estrogen is implicated as an important factor in stimulating breast cancer cell proliferation, and presence of estrogen receptor (ER) is an indication of a good prognosis in breast cancer patients. Mcl-1 is an anti-apoptotic Bcl-2 family member that is often over expressed in breast tumors, correlating with poor survival. In breast cancer, it was been previously shown that epidermal growth factor receptors up-regulate Mcl-1 but the role of estrogen in increasing Mcl-1 expression was unknown. In ERα positive cell lines MCF-7 and ZR-75, estrogen treatment increased Mcl-1 expression at both the protein and mRNA level. In two ERα negative cell lines, SK-BR-3 and MDA-MB-231, estrogen failed to increase in Mcl-1 protein expression. We found that ERα antagonists decreased estrogen mediated Mcl-1 expression at both the protein and mRNA level. Upon knockdown of ERα, Mcl-1 mRNA expression after estrogen treatment was also decreased. We also found that ERα binds to the Mcl-1 promoter at a region upstream of the translation start site containing a half ERE site. Streptavidin-pull down assay showed that both ERα and transcription factor Sp1 bind to this region. These results suggest that estrogen is involved in regulating Mcl-1 expression specifically through a mechanism involving ERα.
Frequent Occurrence of Highly Expanded but Unrelated B-Cell Clones in Patients with Multiple Myeloma
Jitra Kriangkum, Sarah N. Motz, Carina S. Debes Marun, Sandrine T. Lafarge, Spencer B. Gibson, Christopher P. Venner, James B. Johnston, Andrew R. Belch, Linda M. Pilarski
PLOS ONE , 2013, DOI: 10.1371/journal.pone.0064927
Abstract: Clonal diversity in multiple myeloma (MM) includes both MM-related and MM-unrelated clonal expansions which are subject to dominance exerted by the MM clone. Here we show evidence for the existence of minor but highly expanded unrelated B-cell clones in patients with MM defined by their complementary determining region 3 (CDR3) peak. We further characterize these clones over the disease and subsequent treatment. Second clones were identified by their specific IgH-VDJ sequences that are distinct from those of dominant MM clones. Clonal frequencies were determined through semi-quantitative PCR, quantitative PCR and single-cell polymerase chain reaction of the clone-specific sequence. In 13/74 MM patients, more than one dominant CDR3 peak was identified with 12 patients (16%) being truly biclonal. Second clones had different frequencies, were found in different locations and were found in different cell types from the dominant MM clone. Where analysis was possible, they were shown to have chromosomal characteristic distinct from those of the MM clone. The frequency of the second clone also changed over the course of the disease and often persisted despite treatment. Molecularly-defined second clones are infrequent in monoclonal gammopathy of undetermined significance (MGUS, 1/43 individuals or 2%), suggesting that they may arise at relatively late stages of myelomagenesis. In further support of our findings, biclonal gammopathy and concomitant MM and CLL (chronic lymphocytic leukemia) were confirmed to originate from two unrelated clones. Our data supports the idea that the clone giving rise to symptomatic myeloma exerts clonal dominance to prevent expansion of other clones. MM and second clones may arise from an underlying niche permissive of clonal expansion. The clinical significance of these highly expanded but unrelated clones remains to be confirmed. Overall, our findings add new dimensions to evaluating related and unrelated clonal expansions in MM and the impact of disease evolution and treatment on clonal diversity.
A Measurement of the Branching Ratio and Form Factor of K_L->mu mu gamma
M. B. Spencer et. al
Physics , 1995, DOI: 10.1103/PhysRevLett.74.3323
Abstract: We report on a measurement of the decay $K_L\rightarrow\mu^+\mu^-\gamma$ from Fermilab experiment E799. We observe $207$ candidate signal events with an estimated background of $10.5 \pm 4.0$ events and establish $B(K_L\rightarrow\mu^+\mu^-\gamma) = (3.23\pm 0.23(stat) \pm 0.19(sys))\times 10^{-7}$. This provides the first measurement of the $K\gamma\gamma^*$ form factor in the muonic Dalitz decay mode of the $K_L$.
Galaxy evolution: the effect of dark matter on the chemical evolution of ellipticals and galaxy clusters
F. Matteucci,B. K. Gibson
Physics , 1996,
Abstract: In this paper we discuss the chemical evolution of elliptical galaxies and its consequences on the evolution of the intracluster medium (ICM). We use chemical evolution models taking into account dark matter halos and compare the results with previous models where dark matter was not considered. In particular, we examine the evolution of the abundances of some relevant heavy elements such as oxygen, magnesium and iron and conclude that models including dark matter halos and an initial mass function (IMF) containing more massive stars than the Salpeter (1955) IMF, better reproduce the observed abundances of Mg and Fe both in the stellar populations and in the ICM (ASCA results). We also discuss the origin of gas in galaxy clusters and conclude that most of it should have a primordial origin.
Can the $Σ^- nn$ System be Bound?
A. Stadler,B. F. Gibson
Physics , 1994, DOI: 10.1103/PhysRevC.50.512
Abstract: Motivated by the $\Sigma$-hypernuclear states reported in ($K^-,\pi^{\pm}$) experiments, we have explored the possibility that there exists a particle-stable $\Sigma^- nn$ bound state. For the J\"ulich \~A hyperon-nucleon, realistic-force model, our calculations yield little reason to expect a positive-parity bound state in either the $J = \frac{1}{2}$ or the $J = \frac{3}{2}$ channels.
Metallicity Gradients in Simulated Disk Galaxies
K. Pilkington,B. K. Gibson
Physics , 2012,
Abstract: The stellar metallicity and abundance ratio gradients from the fiducial late-type galaxy simulation of Stinson et al. (2010) are presented. Over 1-3 scalelengths, gradients are shown to flatten with time, consistent with empirical evidence at high- and low-redshifts. Kinematic effects, including radial migration, though, flatten these intrinsicly steep gradients such that by redshift z=0, the measured gradients of these (now) old stars are flatter than their young counterparts, in contradiction to what is observed locally. Conversely, the stellar [O/Fe] gradient is (to first order) robust against migration, remaining fairly flat for both young and old populations today.
Chemical Evolution of the Carina Dwarf Spheroidal
K. Pilkington,B. K. Gibson
Physics , 2012,
Abstract: We explore a range of chemical evolution models for the Local Group dwarf spheroidal (dSph) galaxy, Carina. A novel aspect of our work is the removal of the star formation history (SFH) as a `free parameter' in the modeling, making use, instead, of its colour-magnitude diagram (CMD)-constrained SFH. By varying the relative roles of galactic winds, re-accretion, and ram-pressure stripping within the modeling, we converge on a favoured scenario which emphasises the respective roles of winds and re-accretion. While our model is successful in recovering most elemental abundance patterns, comparable success is not found for all the neutron capture elements. Neglecting the effects of stripping results in predicted gas fractions approximately two orders of magnitude too high, relative to that observed.
Polyparasitism Is Associated with Increased Disease Severity in Toxoplasma gondii-Infected Marine Sentinel Species
Amanda K. Gibson,Stephen Raverty,Dyanna M. Lambourn,Jessica Huggins,Spencer L. Magargal,Michael E. Grigg
PLOS Neglected Tropical Diseases , 2011, DOI: 10.1371/journal.pntd.0001142
Abstract: In 1995, one of the largest outbreaks of human toxoplasmosis occurred in the Pacific Northwest region of North America. Genetic typing identified a novel Toxoplasma gondii strain linked to the outbreak, in which a wide spectrum of human disease was observed. For this globally-distributed, water-borne zoonosis, strain type is one variable influencing disease, but the inability of strain type to consistently explain variations in disease severity suggests that parasite genotype alone does not determine the outcome of infection. We investigated polyparasitism (infection with multiple parasite species) as a modulator of disease severity by examining the association of concomitant infection of T. gondii and the related parasite Sarcocystis neurona with protozoal disease in wild marine mammals from the Pacific Northwest. These hosts ostensibly serve as sentinels for the detection of terrestrial parasites implicated in water-borne epidemics of humans and wildlife in this endemic region. Marine mammals (151 stranded and 10 healthy individuals) sampled over 6 years were assessed for protozoal infection using multi-locus PCR-DNA sequencing directly from host tissues. Genetic analyses uncovered a high prevalence and diversity of protozoa, with 147/161 (91%) of our sampled population infected. From 2004 to 2009, the relative frequency of S. neurona infections increased dramatically, surpassing that of T. gondii. The majority of T. gondii infections were by genotypes bearing Type I lineage alleles, though strain genotype was not associated with disease severity. Significantly, polyparasitism with S. neurona and T. gondii was common (42%) and was associated with higher mortality and more severe protozoal encephalitis. Our finding of widespread polyparasitism among marine mammals indicates pervasive contamination of waterways by zoonotic agents. Furthermore, the significant association of concomitant infection with mortality and protozoal encephalitis identifies polyparasitism as an important factor contributing to disease severity in marine mammals.
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