The role of the oestrogen receptor in antioestrogen resistant breast cancer

Breast cancers are often treated with antioestrogens, response rates being highest in cancers expressing oestrogen receptors, responsive tumours will however eventually become resistant. This thesis examines the role of altered oestrogen receptors in the development of antioestrogen resistance. Oestiogen receptors are nuclear hormone receptors that on binding oestradiol bind to specific sequences on DNA and are able to modify the rate of transcription of target genes. Antioestrogens competitively bind to the oestrogen receptor displacing oestradiol but are unable to fully activate the receptor. Oestrogen receptors with aberrant properties may lead to antioestrogen resistance and could arise from mutation of the gene or through alternate splicing of exons. Variant oestrogen receptor MRNA arising from alternative splicing of coding exons has been reported in breast cancers. One splice variant lacking exon 5 encodes a truncated receptor, which has constitutive activity in yeast. To explore the role of this variant in antioestrogen resistant breast cancer, stable cell lines expressing the variant on a conditional promoter have been isolated. These clones do not appear to have altered proliferative response to oestrogen or antioestrogens and there is no constitutive induction of oestrogen responsive genes in the presence of splice variant receptor, however modest activity of some reporter constructs is seen. A short region of the hormone binding domain of the receptor has been identified as being important in determining the response of the receptor to ligand, specific mutations leading to loss of oestradiol activation but leading to stimulation of transcription by antioestrogens in HeLa cells. The activity of such mutant receptors has been examined in breast cancer cell lines. Modest agonist activity is seen in transient expression systems and attempts to establish stable expression of mutant receptors are described. A system for the identification of mutations in this region has been used to screen for mutations in human breast cancers. Mutations that alter the ligand binding properties of the receptor have been reported. In order to identify mutations that are unable to bind tamoxifen but are still activated by oestrogen, a yeast screening system was used to screen randomly mutated oestrogen receptors. The properties of mutations identified from this system are described

All Six Planets Known to Orbit Kepler-11 Have Low Densities

The Kepler-11 planetary system contains six transiting planets ranging in size from 1.8 to 4.2 times the radius of Earth. Five of these planets orbit in a tightly-packed configuration with periods between 10 and 47 days. We perform a dynamical analysis of the system based upon transit timing variations observed in more than three years of \ik photometric data. Stellar parameters are derived using a combination of spectral classification and constraints on the star's density derived from transit profiles together with planetary eccentricity vectors provided by our dynamical study. Combining masses of the planets relative to the star from our dynamical study and radii of the planets relative to the star from transit depths together with deduced stellar properties yields measurements of the radii of all six planets, masses of the five inner planets, and an upper bound to the mass of the outermost planet, whose orbital period is 118 days. We find mass-radius combinations for all six planets that imply that substantial fractions of their volumes are occupied by constituents that are less dense than rock. The Kepler-11 system contains the lowest mass exoplanets for which both mass and radius have been measured.Comment: 39 pages, 10 figure

Síndrome de quilomicronemia familiar, deficiencia del factor de maduración de lipasa

. Introducción: el síndrome de quilomicronemia familiar se considera un trastorno autosómico recesivo, poco frecuente, que puede presentarse clínicamente desde la infancia, pero se manifiesta después de su debut a cualquier edad. Clínicamente se presenta con dolor abdominal, pancreatitis aguda recurrente, xantomas cutáneos y hepatoesplomegalia. Por NGS su confirmación precisa que la variante encontrada siempre es bialélica; los progenitores por definición son heterocigotos para la misma variante y no presentan la enfermedad, solo portan la mutación sin presentar síntomas. Objetivo: investigar la presencia de la quilomicronemia y determinar su patrón de herencia, ya sea como una forma familiar con un patrón monogénico bialélico o como una condición de naturaleza multifactorial. Presentación del caso: se presenta el caso de un paciente con múltiples comorbilidades que acude por dolor abdominal e hipertrigliceridemia de etiología no filiada, al cual se le envían estudios genéticos para filiar la etiología y establecer un tratamiento adecuado. Discusión y conclusión: se realiza un estudio genético de análisis molecular por secuenciación de nueva generación, identificado en homocigosis en el gen LMF1. Esta variante se caracteriza por ser patogénica. Para diagnosticar el síndrome de quilomicronemia se deben identificar variantes bialélicas no patogénicas en el complejo LPL y proteínas relacionadas. El tratamiento consiste en la restricción de grasa en la dieta para reducir la morbilidad y mortalidad, así como el seguimiento por parte de genética para el estudio de familiares con riesgo

An Unusual Transmission Spectrum for the Sub-Saturn KELT-11b Suggestive of a Sub-Solar Water Abundance

We present an optical-to-infrared transmission spectrum of the inflated sub-Saturn KELT-11b measured with the Transiting Exoplanet Survey Satellite (TESS), the Hubble Space Telescope (HST) Wide Field Camera 3 G141 spectroscopic grism, and the Spitzer Space Telescope (Spitzer) at 3.6 $\mu$m, in addition to a Spitzer 4.5 $\mu$m secondary eclipse. The precise HST transmission spectrum notably reveals a low-amplitude water feature with an unusual shape. Based on free retrieval analyses with varying molecular abundances, we find strong evidence for water absorption. Depending on model assumptions, we also find tentative evidence for other absorbers (HCN, TiO, and AlO). The retrieved water abundance is generally $\lesssim 0.1\times$ solar (0.001--0.7$\times$ solar over a range of model assumptions), several orders of magnitude lower than expected from planet formation models based on the solar system metallicity trend. We also consider chemical equilibrium and self-consistent 1D radiative-convective equilibrium model fits and find they too prefer low metallicities ($[M/H] \lesssim -2$, consistent with the free retrieval results). However, all the retrievals should be interpreted with some caution since they either require additional absorbers that are far out of chemical equilibrium to explain the shape of the spectrum or are simply poor fits to the data. Finally, we find the Spitzer secondary eclipse is indicative of full heat redistribution from KELT-11b's dayside to nightside, assuming a clear dayside. These potentially unusual results for KELT-11b's composition are suggestive of new challenges on the horizon for atmosphere and formation models in the face of increasingly precise measurements of exoplanet spectra.Comment: Accepted to The Astronomical Journal. 31 pages, 20 figures, 7 table

Bicycle Friendly Community Assessment Spring 2015

Completed by Cal Poly, San Luis Obispo City & Regional Planning students enrolled in a bicycle and pedestrian planning course (CRP 425), under the direction of Dr. William Riggs this report was designed to gather data in advance of the City of San Luis Obispo\u27s application to be a Bicycle Friendly Community. The report focuses on the key certification areas of Engineering, Education, Encouragement, Evaluation/Planning and Enforcement providing documentation for the City\u27s eventual application

Masses, radii, and orbits of small Kepler planets : The transition from gaseous to rocky planets

We report on the masses, sizes, and orbits of the planets orbiting 22 Kepler stars. There are 49 planet candidates around these stars, including 42 detected through transits and 7 revealed by precise Doppler measurements of the host stars. Based on an analysis of the Kepler brightness measurements, along with high-resolution imaging and spectroscopy, Doppler spectroscopy, and (for 11 stars) asteroseismology, we establish low false-positive probabilities (FPPs) for all of the transiting planets (41 of 42 have an FPP under 1%), and we constrain their sizes and masses. Most of the transiting planets are smaller than three times the size of Earth. For 16 planets, the Doppler signal was securely detected, providing a direct measurement of the planet's mass. For the other 26 planets we provide either marginal mass measurements or upper limits to their masses and densities; in many cases we can rule out a rocky composition. We identify six planets with densities above 5 g cm-3, suggesting a mostly rocky interior for them. Indeed, the only planets that are compatible with a purely rocky composition are smaller than 2 R ⊕. Larger planets evidently contain a larger fraction of low-density material (H, He, and H2O).Peer reviewedFinal Accepted Versio

A super-earth-sized planet orbiting in or near the habitable zone around a sun-like star

We present the discovery of a super-Earth-sized planet in or near the habitable zone of a Sun-like star. The host is Kepler-69, a 13.7 mag G4V-type star. We detect two periodic sets of transit signals in the 3-year flux time series of Kepler-69, obtained with the Kepler spacecraft. Using the very high precision Kepler photometry, and follow-up observations, our confidence that these signals represent planetary transits is >99.3%. The inner planet, Kepler-69b, has a radius of R⊕ and orbits the host star every 13.7 days. The outer planet, Kepler-69c, is a super-Earth-sized object with a radius of R⊕ and an orbital period of 242.5 days. Assuming an Earth-like Bond albedo, Kepler-69c has an equilibrium temperature of 299 ± 19 K, which places the planet close to the habitable zone around the host star. This is the smallest planet found by Kepler to be orbiting in or near the habitable zone of a Sun-like star and represents an important step on the path to finding the first true Earth analog