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Search Results: 1 - 10 of 9890 matches for " Patrick Guinan "
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Following Inhibition of BCL-2 by Antisense Oligonucleotides Compensatory Suppression of Apoptosis Involves the Direct Signal Transduction Pathway of LNCaP Cells  [PDF]
Marvin Rubenstein, Courtney M. P. Hollowell, Patrick Guinan
Open Journal of Apoptosis (OJApo) , 2015, DOI: 10.4236/ojapo.2015.41001
Abstract: Previously we have shown that when LNCaP cells are treated with antisense oligonucleotides (oligos) directed against BCL-2, compensatory changes in non-targeted genes take place in attempts to restore apoptosis and promote tumor aggressiveness. In addition to the inhibition of BCL-2, we find that the apoptosis promoter caspase-3 activity is suppressed, the transcription activity of STAT-3 is enhanced, while other regulators (bax, clusterin, AKT-1) associated with mitochondrial regulated apoptosis and caspase cascade are either unchanged or undetectable. We now evaluate proteins associated with the second pathway of apoptosis activation mediated by direct signal transduction involving fas, fas-ligand (a tumor necrosis factor-like cell surface receptor aka CD95), as well as the similar programmed death cell surface receptor (PD-1) and its respective ligand (PD-1L). This study evaluates the growth inhibition of in vitro propagating LNCaP cells employing mono- and bispecific oligos directed against BCL-2 [the second binding site was directed against the epidermal growth factor receptor (EGFR)]; and employing RT-PCR. The expression of these four proteins was evaluated. Expression of fas-ligand, PD-1 and PD-L1 were all significantly enhanced, whereas fas itself was undetectable. This suggests that in addition to pathways associated with the mitochondrial pathway of apoptosis, compensatory changes occur in the direct signal transduction pathway of this process. In addition to alterations in androgen sensitivity, growth factor expression and oncogene expression, these data suggest that suppressive BCL-2 therapy involves multiple pathways, including those involved with immune targeting and cytotoxicity and must be taken into account to make gene therapy more efficacious.
Altered Oncogene Activity Contributes to Compensation for Antisense Suppression of Bcl-2 and Tumor Resistance  [PDF]
Marvin Rubenstein, Courtney M. P. Hollowell, Patrick Guinan
Open Journal of Apoptosis (OJApo) , 2015, DOI: 10.4236/ojapo.2015.43007
Abstract: Antisense oligonucleotides (oligos) have targeted growth regulatory proteins in prostate cancer models. To identify compensatory alterations in the expression of non-targeted genes we evaluate mono- and bispecific oligos targeting and equally suppressing the expression of the apoptosis inhibitory protein bcl-2. Bcl-2 is chosen because oligos directed towards it have entered clinical trials to restore apoptosis in cancer patients. Treated LNCaP cells compensate for the diminished bcl-2 by suppressing caspase-3 (an apoptosis promoter) while enhancing expression of AKT-1 (another apoptosis inhibitor), androgen receptor (AR) and its (p300 and IL-6) coactivators. Additional proteins are enhanced including PD-1, its ligand PD-L1 (immune checkpoint blockade markers) and fas-ligand, which activate apoptosis through the signal transduction, along with suppressor protein p53, polymerase transcription mediator MED-12 and signal transducer STAT-3. These alterations in expression may contribute to a greatly enhanced expression of the proliferation marker KI-67. This suggests that therapeutic approaches to restore apoptosis through suppression of bcl-2 lead to an altered expression in non-targeted genes involving apoptosis, androgen sensitivity, transcriptional activity and immune responsiveness, leads to an increase in proliferation (and a more androgen driven aggressive phenotype). In this study we evaluate the expression of two oncogenes (v-myc and K-ras) and find a large and significant enhancement of v-myc activity, which is produced by oligos targeting bcl-2 at the 5’ position. For K-ras, although significant suppression is produced by the bispecific targeting bcl-2 at the 3’ position, the percent change is relatively small compared with other compensatory alterations we have measured, and much less than in v-myc. Therefore, for the two oncogenes being evaluated, only increased v-myc activity is probably large enough to contribute to increased tumor aggressiveness in compensation for bcl-2 suppression.
Correlation Between PSMA and VEGF Expression as Markers for LNCaP Tumor Angiogenesis
Paulus Tsui,Marvin Rubenstein,Patrick Guinan
Journal of Biomedicine and Biotechnology , 2005, DOI: 10.1155/jbb.2005.287
Abstract: Our aim is the identification and correlation of changes in tumor-associated protein expression which results from therapy. LNCaP tumors, excised from nude mice treated either by orchiectomy or with the chemotherapeutic agent paclitaxel, were evaluated for the expression of proteins and receptors associated with growth, differentiation, and angiogenesis using immunohistologic procedures. Compared to untreated control tumors, both treatments reduced the expression of vascular endothelial growth factor (VEGF), prostate-specific membrane antigen (PSMA), prostate-specific antigen (PSA), androgen receptor (AR), and epidermal growth factor receptor (EGFR). The effect of paclitaxel treatment on AR expression was the most significant (P=.005). Of particular interest was identifying a significant correlation (P<.000801) between PSMA and VEGF expression regardless of treatment modality. These altered expressions suggest that PSMA may also be a marker for angiogenesis and could represent a target for deliverable agents recognizing either prostatic tumors or endothelial development. Cell surface PSMA would then present a unique target for treatment of patients early in their development of prostatic metastases.
Correlation Between PSMA and VEGF Expression as Markers for LNCaP Tumor Angiogenesis
Tsui Paulus,Rubenstein Marvin,Guinan Patrick
Journal of Biomedicine and Biotechnology , 2005,
Abstract: Our aim is the identification and correlation of changes in tumor-associated protein expression which results from therapy. LNCaP tumors, excised from nude mice treated either by orchiectomy or with the chemotherapeutic agent paclitaxel, were evaluated for the expression of proteins and receptors associated with growth, differentiation, and angiogenesis using immunohistologic procedures. Compared to untreated control tumors, both treatments reduced the expression of vascular endothelial growth factor (VEGF), prostate-specific membrane antigen (PSMA), prostate-specific antigen (PSA), androgen receptor (AR), and epidermal growth factor receptor (EGFR). The effect of paclitaxel treatment on AR expression was the most significant ( P = .005 ) . Of particular interest was identifying a significant correlation ( P < .000801 ) between PSMA and VEGF expression regardless of treatment modality. These altered expressions suggest that PSMA may also be a marker for angiogenesis and could represent a target for deliverable agents recognizing either prostatic tumors or endothelial development. Cell surface PSMA would then present a unique target for treatment of patients early in their development of prostatic metastases.
Summary of IAU colloquium 191: the environment and Evolution of binary and multiple stars
Edward F. Guinan
Revista mexicana de astronomía y astrofísica , 2004,
Abstract: Se presenta un resumen del Coloquio 191 de la UAI El Entorno y la Evoluci on de las Estrellas Binarias y M ultiples". Esta conferencia se celebr o en M erida, M exico, en febrero de 2003, y estuvo dedicada al Dr. Arcadio Poveda, por sus importantes contribuciones al campo de las estrellas binarias y m ultiples y su din amica. La conferencia se organiz o para discutir los principales desarrollos que est an ocurriendo en los campos de formaci on de binarias y m ultiples, su evoluci on, su din amica y el entorno en donde se forman y evolucionan.
The Best Brown Dwarf Yet?: A Companion to the Hyades Eclipsing Binary V471 Tau
Edward F. Guinan,Ignasi Ribas
Physics , 2000, DOI: 10.1086/318065
Abstract: We have carried out an analysis of about 160 eclipse timings spanning over 30 years of the Hyades eclipsing binary V471 Tauri that shows a long-term quasi-sinusoidal modulation of its observed eclipse arrival times. The O-Cs have been analyzed for the ``light-time'' effect that arises from the gravitational influence of a tertiary companion. The presence of a third body causes the relative distance of the eclipsing pair to the Earth to change as it orbits the barycenter of the triple system. The result of the analysis of the eclipse times yields a light-time semi-amplitude of 137.2+/-12.0 s, an orbital period of P_3 = 30.5+/-1.6 yr and an eccentricity of e_3 = 0.31+/-0.04. The mass of the tertiary component is M_3 sin i_3 = 0.0393+/-0.0038 Mo when a total mass of 1.61+/-0.06 Mo for V471 Tau is adopted. For orbital inclinations i_3 > 35 deg, the mass of the third body would be below the stable hydrogen burning limit of M = 0.07 Mo and it thus would be a brown dwarf. In the next several years (near maximum elongation), it should be feasible to obtain IR images and spectra of V471 Tau C that, when combined with the known mass, age, distance, and [Fe/H], will serve as a benchmark for understanding the physical properties and evolution of brown dwarfs.
The "Living with a Red Dwarf" Program
Edward F. Guinan,Scott G. Engle
Physics , 2009,
Abstract: Red Dwarfs (main-sequence / dwarf M or dM) stars are the most common stars in the Galaxy. These cool, faint, low mass stars comprise over 75% of all stars. Because of their low luminosities (~0.0008-0.06 of the Sun's luminosity), the circumstellar habitable zones (HZs) of dM stars are located within ~0.05-0.4 AU of the host star. Nevertheless, the prospect of life on a planet located within the HZ of a red dwarf is moderately high, based on the longevity of these stars (>50 Gyr), their constant luminosities and high space densities. Here we describe the aims and early results of the "Living with a Red Dwarf" Program - a study of dM stars that we have been carrying out over the last few years. The primary focus of our research on dM stars is the study of their magnetic dynamos and resulting star spots & coronal X-ray and chromospheric UV emissions as a function of age, rotation and spectral type. This program will provide datasets that can be used as inputs for the study of all aspects of dM stars, along with the planets already discovered hosted by them and the probable hundreds (thousands?) of planets expected to be uncovered in the near future by missions such as Kepler & Darwin/TPF. These datasets will be invaluable to those who model exo-planetary atmospheres, as well as exobiologists & astrobiologists who are studying the possibilities of life elsewhere in the universe. A significant element of our program is the determination of accurate stellar magnetic-driven X-ray-UV (X-UV) irradiances that are generated by the dM stars' vigorous magnetic dynamos. These X-UV irradiances (and flare frequencies) are strongly dependent on rotation, and thus age, and diminish as the stars lose angular momentum and spin-down over time via magnetic braking.
Astrometric and Light-travel Time Orbits to Detect Low-mass Companions: A Case Study of the Eclipsing System R Canis Majoris
Ignasi Ribas,Frederic Arenou,Edward F. Guinan
Physics , 2002, DOI: 10.1086/339560
Abstract: We discuss a method to determine orbital properties and masses of low-mass bodies orbiting eclipsing binaries. The analysis combines long-term eclipse timing modulations (light-travel time or LTT effect) with short-term, high-accuracy astrometry. As an illustration of the method, the results of a comprehensive study of Hipparcos astrometry and over a hundred years of eclipse timings of the Algol-type eclipsing binary R Canis Majoris are presented. A simultaneous solution of the astrometry and the LTTs yields an orbital period of P_12=92.8+/-1.3 yr, an LTT semiamplitude of 2574+/-57 s, an angular semi-major axis of a_12=117+/-5 mas, and values of the orbital eccentricity and inclination of e_12=0.49+/-0.05, and i_12=91.7+/-4.7 deg, respectively. Adopting the total mass of R CMa of M_12=1.24+/-0.05 Mo, the mass of the third body is M_3=0.34+/-0.02 Mo and the semi-major axis of its orbit is a_3=18.7+/-1.7 AU. From its mass, the third body is either a dM3-4 star or, more unlikely, a white dwarf. With the upcoming microarcsecond-level astrometric missions, the technique that we discuss can be successfully applied to detect and characterize long-period planetary-size objects and brown dwarfs around eclipsing binaries. Possibilities for extending the method to pulsating variables or stars with transiting planets are briefly addressed.
Red Dwarf Stars: Ages, Rotation, Magnetic Dynamo Activity and the Habitability of Hosted Planets
Scott G. Engle,Edward F. Guinan
Physics , 2011,
Abstract: We report on our continued efforts to understand and delineate the magnetic dynamo-induced behavior/variability of red dwarf (K5 V - M6 V) stars over their long lifetimes. These properties include: rotation, light variations (from star spots), coronal-chromospheric XUV activity and flares. This study is being carried out as part of the NSF-sponsored Living with a Red Dwarf program. The Living with a Red Dwarf program's database of dM stars with photometrically determined rotation rates (from starspot modulations) continues to expand, as does the inventory of archival XUV observations. When all data sets are combined with ages from cluster/population memberships and kinematics, the determination of Age-Rotation-Activity relationships is possible. Such relationships have broad impacts not only on the studies of magnetic dynamo theory & angular momentum loss of low-mass stars with deep convective zones, but also on the suitability of planets hosted by red dwarfs to support life. With intrinsically low luminosities (L < 0.02L_sun), the liquid water habitable zones (HZs) for hosted planets are very close to their host stars - typically at ~0.1-0.4 AU. Planets located close to their host stars risk damage and atmospheric loss from coronal & chromospheric XUV radiation, flares and plasma blasts via strong winds and coronal mass ejections. In addition, our relationships permit the stellar ages to be determined through measures of either the stars' rotation periods (best way) or XUV activity levels. This also permits a determination of the ages of their hosted planets. We illustrate this with examples of age determinations of the exoplanet systems: GJ 581 and HD 85512 (both with large Earth-size planets within the host star's HZ), GJ 1214 (hot, close-in transiting super-Earth planet) and HD 189733 (short period, hot-Jupiter planet interacting with its host star - age from its dM4 star companion).
The Sun in Time: Age, Rotation, and Magnetic Activity of the Sun and Solar-type Stars and Effects on Hosted Planets
Edward F. Guinan,Scott G. Engle
Physics , 2009, DOI: 10.1017/S1743921309032050
Abstract: Multi-wavelength studies of solar analogs (G0-5 V stars) with ages from ~50 Myr to 9 Gyr have been carried out as part of the "Sun in Time" program for nearly 20 yrs. From these studies it is inferred that the young (ZAMS) Sun was rotating more than 10x faster than today. As a consequence, young solar-type stars and the early Sun have vigorous magnetohydrodynamic (MHD) dynamos and correspondingly strong coronal X-ray and transition region / chromospheric FUV-UV emissions. To ensure continuity and homogeneity for this program, we use a restricted sample of G0-5 V stars with masses, radii, T(eff), and internal structure (i.e. outer convective zones) closely matching those of the Sun. From these analogs we have determined reliable rotation-age-activity relations and X-ray - UV (XUV) spectral irradiances for the Sun (or any solar-type star) over time. These XUV irradiance measures serve as input data for investigating the photo-ionization and photo-chemical effects of the young, active Sun on the paleo-planetary atmospheres and environments of solar system planets. These measures are also important to study the effects of these high energy emissions on the numerous exoplanets hosted by solar-type stars of different ages. Recently we have extended the study to include lower mass, main-sequence (dwarf) dK and dM stars to determine relationships among their rotation spin-down rates and coronal and chromospheric emissions as a function of mass and age. From rotation-age-activity relations we can determine reliable ages for main-sequence G, K, M field stars and, subsequently, their hosted planets. Also inferred are the present and the past XUV irradiance and plasma flux exposures that these planets have endured and the suitability of the hosted planets to develop and sustain life.
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