The MultiSite Spectroscopic Telescope campaign: 2m spectroscopy of the V361 Hya variable PG1605+072

We present results and analysis for the 2m spectroscopic part of the MultiSite Spectroscopic Telescope (MSST) campaign undertaken in May/June 2002. The goal of the project was to observe the pulsating subdwarf B star PG1605+072 simultaneously in velocity and photometry and to resolve as many of the >50 known modes as possible, which will allow a detailed asteroseismological analysis. We have obtained over 150 hours of spectroscopy, leading to an unprecedented noise level of only 207m/s. We report here the detection of 20 frequencies in velocity, with two more likely just below our detection threshold. In particular, we detect 6 linear combinations, making PG1605+072 only the second star known to show such frequencies in velocity. We investigate the phases of these combinations and their parent modes and find relationships between them that cannot be easily understood based on current theory. These observations, when combined with our simultaneous photometry, should allow asteroseismology of this most complicated of sdB pulsators.Comment: 9 pages, 5 figures, accepted for publication in A&A; Figure 1 at lower resolution than accepted versio

Radial velocity variations of the pulsating subdwarf B star PG 1605+072

We present an analysis of high-speed spectroscopy of the pulsating subdwarf B star PG 1605+072. Periodic radial motions are detected at frequencies similar to those reported for photometric variations in the star, with amplitudes of up to 6 km/s. Differences between relative strengths for given frequency peaks for our velocity data and previously measured photometry are probably a result of shifting of power between modes over time. Small differences in the detected frequencies may also indicate mode-shifting. We report the detection of line-shape variations using the moments of the cross correlation function profiles. It may be possible to use the moments to identify the star's pulsation modes.Comment: 5 pages, 6 figure

The molecular genetic analysis of the expanding pachyonychia congenita case collection

BACKGROUND: Pachyonychia congenita (PC) is a rare autosomal dominant keratinizing disorder characterized by severe, painful, palmoplantar keratoderma and nail dystrophy, often accompanied by oral leucokeratosis, cysts and follicular keratosis. It is caused by mutations in one of five keratin genes: KRT6A, KRT6B, KRT6C, KRT16 or KRT17. OBJECTIVES: To identify mutations in 84 new families with a clinical diagnosis of PC, recruited by the International Pachyonychia Congenita Research Registry during the last few years. METHODS: Genomic DNA isolated from saliva or peripheral blood leucocytes was amplified using primers specific for the PC-associated keratin genes and polymerase chain reaction products were directly sequenced. RESULTS: Mutations were identified in 84 families in the PC-associated keratin genes, comprising 46 distinct keratin mutations. Fourteen were previously unreported mutations, bringing the total number of different keratin mutations associated with PC to 105. CONCLUSIONS: By identifying mutations in KRT6A, KRT6B, KRT6C, KRT16 or KRT17, this study has confirmed, at the molecular level, the clinical diagnosis of PC in these families

Identifying novel hypoxia-associated markers of chemoresistance in ovarian cancer

BACKGROUND Ovarian cancer is associated with poor long-term survival due to late diagnosis and development of chemoresistance. Tumour hypoxia is associated with many features of tumour aggressiveness including increased cellular proliferation, inhibition of apoptosis, increased invasion and metastasis, and chemoresistance, mostly mediated through hypoxia-inducible factor (HIF)-1α. While HIF-1α has been associated with platinum resistance in a variety of cancers, including ovarian, relatively little is known about the importance of the duration of hypoxia. Similarly, the gene pathways activated in ovarian cancer which cause chemoresistance as a result of hypoxia are poorly understood. This study aimed to firstly investigate the effect of hypoxia duration on resistance to cisplatin in an ovarian cancer chemoresistance cell line model and to identify genes whose expression was associated with hypoxia-induced chemoresistance. METHODS Cisplatin-sensitive (A2780) and cisplatin-resistant (A2780cis) ovarian cancer cell lines were exposed to various combinations of hypoxia and/or chemotherapeutic drugs as part of a 'hypoxia matrix' designed to cover clinically relevant scenarios in terms of tumour hypoxia. Response to cisplatin was measured by the MTT assay. RNA was extracted from cells treated as part of the hypoxia matrix and interrogated on Affymetrix Human Gene ST 1.0 arrays. Differential gene expression analysis was performed for cells exposed to hypoxia and/or cisplatin. From this, four potential markers of chemoresistance were selected for evaluation in a cohort of ovarian tumour samples by RT-PCR. RESULTS Hypoxia increased resistance to cisplatin in A2780 and A2780cis cells. A plethora of genes were differentially expressed in cells exposed to hypoxia and cisplatin which could be associated with chemoresistance. In ovarian tumour samples, we found trends for upregulation of ANGPTL4 in partial responders and down-regulation in non-responders compared with responders to chemotherapy; down-regulation of HER3 in partial and non-responders compared to responders; and down-regulation of HIF-1α in non-responders compared with responders. CONCLUSION This study has further characterized the relationship between hypoxia and chemoresistance in an ovarian cancer model. We have also identified many potential biomarkers of hypoxia and platinum resistance and provided an initial validation of a subset of these markers in ovarian cancer tissues

Population preference values for treatment outcomes in chronic lymphocytic leukaemia: a cross-sectional utility study

<p>Abstract</p> <p>Background</p> <p>Given that treatments for chronic lymphocytic leukaemia (CLL) are palliative rather than curative, evaluating the patient-perceived impacts of therapy is critical. To date, no utility (preference) studies from the general public or patient perspective have been conducted in CLL. The objective of this study was to measure preferences for health states associated with CLL treatment.</p> <p>Methods</p> <p>This was a cross-sectional study of 89 members of the general population in the UK (England and Scotland). Using standard gamble, each participant valued four health states describing response status, six describing treatment-related toxicities based on Common Toxicity Criteria, and two describing line of treatment. The health states incorporated standardized descriptions of treatment response (symptoms have "improved," "stabilized," or "gotten worse"), swollen glands, impact on daily activities, fatigue, appetite, and night sweats. Utility estimates ranged from 0.0, reflecting dead, to 1.0, reflecting full health.</p> <p>Results</p> <p>Complete response (CR) was the most preferred health state (mean utility, 0.91), followed by partial response (PR), 0.84; no change (NC), 0.78; and progressive disease (PD), 0.68. Among the toxicity states, grade I/II nausea and nausea/vomiting had the smallest utility decrements (both were -0.05), and grade III/IV pneumonia had the greatest decrement (-0.20). The utility decrements obtained for toxicity states can be subtracted from utilities for CR, PR, NC, and PD, as appropriate. The utilities for second- and third-line treatments, which are attempted when symptoms worsen, were 0.71 and 0.65, respectively. No significant differences in utilities were observed by age, sex, or knowledge/experience with leukaemia.</p> <p>Conclusions</p> <p>This study reports UK population utilities for a universal set of CLL health states that incorporate intended treatment response and unintended toxicities. These utilities can be applied in future cost-effectiveness analyses of CLL treatment.</p

Methods for exomoon characterisation: combining transit photometry and the Rossiter-McLaughlin effect

It has been suggested that moons around transiting exoplanets may cause observable signal in transit photometry or in the Rossiter-McLaughlin (RM) effect. In this paper a detailed analysis of parameter reconstruction from the RM effect is presented for various planet-moon configurations, described with 20 parameters. We also demonstrate the benefits of combining photometry with the RM effect. We simulated 2.7x10^9 configurations of a generic transiting system to map the confidence region of the parameters of the moon, find the correlated parameters and determine the validity of reconstructions. The main conclusion is that the strictest constraints from the RM effect are expected for the radius of the moon. In some cases there is also meaningful information on its orbital period. When the transit time of the moon is exactly known, for example, from transit photometry, the angle parameters of the moon's orbit will also be constrained from the RM effect. From transit light curves the mass can be determined, and combining this result with the radius from the RM effect, the experimental determination of the density of the moon is also possible.Comment: 10 pages, 7 figures, accepted for publication in MNRA

Three ways to solve the orbit of KIC11558725: a 10 day beaming sdB+WD binary with a pulsating subdwarf

The recently discovered subdwarf B (sdB) pulsator KIC11558725 features a rich g-mode frequency spectrum, with a few low-amplitude p-modes at short periods, and is a promising target for a seismic study aiming to constrain the internal structure of this star, and of sdB stars in general. We have obtained ground-based spectroscopic Balmer-line radial-velocity measurements of KIC11558725, spanning the 2010 and 2011 observing seasons. From these data we have discovered that KIC11558725 is a binary with period P=10.05 d, and that the radial-velocity amplitude of the sdB star is 58 km/s. Consequently the companion of the sdB star has a minimum mass of 0.63 M\odot, and is therefore most likely an unseen white dwarf. We analyse the near-continuous 2010-2011 Kepler light curve to reveal orbital Doppler-beaming light variations at the 238 ppm level, which is consistent with the observed spectroscopic orbital radial-velocity amplitude of the subdwarf. We use the strongest 70 pulsation frequencies in the Kepler light curve of the subdwarf as clocks to derive a third consistent measurement of the orbital radial-velocity amplitude, from the orbital light-travel delay. We use our high signal-to-noise average spectra to study the atmospheric parameters of the sdB star, deriving Teff = 27 910K and log g = 5.41 dex, and find that carbon, nitrogen and oxygen are underabundant relative to the solar mixture. Furthermore, we extract more than 160 significant frequencies from the Kepler light curve. We investigate the pulsation frequencies for expected period spacings and rotational splittings. We find period-spacing sequences of spherical-harmonic degrees \ell=1 and \ell=2, and we associate a large fraction of the g-modes in KIC11558725 with these sequences. From frequency splittings we conclude that the subdwarf is rotating subsynchronously with respect to the orbit

Oncometabolite induced primary cilia loss in pheochromocytoma

Primary cilia are sensory organelles involved in regulation of cellular signaling. Cilia loss is frequently observed in tumors; yet, the responsible mechanisms and consequences for tumorigenesis remain unclear. We demonstrate that cilia structure and function is disrupted in human pheochromocytomas – endocrine tumors of the adrenal medulla. This is concomitant with transcriptional changes within cilia-mediated signaling pathways that are associated with tumorigenesis generally and pheochromocytomas specifically. Importantly, cilia loss was most dramatic in patients with germline mutations in the pseudohypoxia-linked genes SDHx and VHL. Using a pheochromocytoma cell line derived from rat, we show that hypoxia and oncometabolite-induced pseudohypoxia are key drivers of cilia loss and identify that this is dependent on activation of an Aurora-A/HDAC6 cilia resorption pathway. We also show cilia loss drives dramatic transcriptional changes associated with proliferation and tumorigenesis. Our data provide evidence for primary cilia dysfunction contributing to pathogenesis of pheochromocytoma by a hypoxic/pseudohypoxic mechanism and implicates oncometabolites as ciliary regulators. This is important as pheochromocytomas can cause mortality by mechanisms including catecholamine production and malignant transformation, while hypoxia is a general feature of solid tumors. Moreover, pseudohypoxia-induced cilia resorption can be pharmacologically inhibited, suggesting potential for therapeutic intervention

Thermodynamic analysis of 5′ and 3′ single- and 3′ double-nucleotide overhangs neighboring wobble terminal base pairs

Thermodynamic parameters are reported for duplex formation of 40 self-complementary RNA duplexes containing wobble terminal base pairs with all possible 3′ single and double-nucleotide overhangs, mimicking the structures of short interfering RNAs (siRNA) and microRNAs (miRNA). Based on nearest neighbor analysis, the addition of a single 3′ dangling nucleotide increases the stability of duplex formation up to 1 kcal/mol in a sequence-dependent manner. The addition of a second dangling nucleotide increases the stability of duplexes closed with wobble base pairs in an idiosyncratic manner. The results allow for the development of a nearest neighbor model, which improves the predication of free energy and melting temperature for duplexes closed by wobble base pairs with 3′ single or double-nucleotide overhangs. Phylogenetic analysis of naturally occurring miRNAs was performed. Selection of the effector miR strand of the mature miRNA duplex appears to be dependent on the orientation of the GU closing base pair rather than the identity of the 3′ double-nucleotide overhang. Thermodynamic parameters for the 5′ single terminal overhangs adjacent to wobble closing base pairs are also presented

Time-series Spectroscopy and Photometry of the Pulsating Subdwarf B Star PG 1219+534 (KY UMa)

We present observations and analysis of time-series spectroscopy and photometry of the pulsating subdwarf B star PG 1219+534 (KY UMa). Subdwarf B stars are blue horizontal branch stars which have shed most of their hydrogen envelopes. Pulsating subdwarf B stars allow a probe into this interesting phase of evolution. Low resolution spectra were obtained at the Nordic Optical Telescope and Kitt Peak National Observatory, and photometric observations were obtained at MDM and Baker observatories in 2006. We extracted radial velocity and equivalent width variations from several Balmer and He I lines in individual spectra. The pulsation frequencies were separated via phase binning to detect line-profile variations in Balmer and helium lines, which were subsequently matched to atmospheric models to infer effective temperature and gravity changes throughout the pulsation cycle. From the photometry we recovered the four previously observed frequencies and detected a new fifth frequency. From the spectra we directly measured radial velocity and equivalent width variations for the four main frequencies and from atmospheric models we successfully inferred temperature and gravity changes for these four frequencies. We compared amplitude ratios and phase differences of these quantities and searched for outliers which could be identified as high-degree modes. These are the first such measurements for a "normal" amplitude pulsating subdwarf B star, indicating that spectroscopic studies can benefit the majority of pulsating subdwarf B stars.Comment: 9 pages, 13 figures accepted for publication in Astronomy & Astrophysic