Molecular tumor profiling: translating genomic insights into clinical advances

Molecular profiling of the transcripts or proteins within an individual tumor may in future provide important prognostic and therapeutic clinical information both for the affected individual and for their extended family, but for the time being traditional genetics and pathology retain their place in the clinic

Investigation into the potential of tissue-specific promoters for gene supplementation therapy

Ornithine transcarbamylase (OTC) is the second enzyme in the hepatic urea cycle. As such, it is important in the metabolism of neurotoxic waste products into a non-toxic, water-soluble compound, urea. In humans deficiency of ornithine transcarbamylase is an X-linked single gene disorder associated with a high mortality and morbidity due to a severe metabolic disturbance. There are two naturally occuring allelic mouse models for OTC deficiency, the sparse fur (Spf) and sparse furASH (SpfASH) mice. In this study, the focus was on the use of tissue specific promoters in driving recombinant gene expression. The main question addressed was whether expression of the OTC gene in a tissue which did not normally express this gene, namely skeletal muscle, would correct the phenotype of the deficient mouse models. The approach taken was generation of conventional transgenic mice using a creatine kinase driven OTC gene construct. In addition as a positive control, supplementation of the endogenous hepatic gene expression was also undertaken by means of hepatic-specific albumin promoter. Three indices were used as a measure of correction of OTC deficiency by transgenesis in the mouse models; a) phenotype of the mice, b) plasma ammonia levels and c) direct OTC activity. Although transgenic mice expressing the OTC cDNA driven by the creatine kinase promoter showed high OTC activity in skeletal muscle, no metabolic or phenotypic correction of the mice was noted. Interestingly, the albumin driven OTC construct did not correct the phenotype of the sparse fur and sparse furASH models either, although in some transgenic lines a significant amelioration of plasma ammonia levels was noted. However, this partial metabolic correction did not correlate with a significant increase in hepatic OTC activity. In addition to these tissue-specific promoters, the potential of a novel keratin 5 minigene construct in targeting recombinant gene expression to the epidermis in a tissue and cell specific manner was assessed. The gene expression pattern of a Lac Z reporter transgenic construct driven by the regulatory sequences of the keratin 5 gene was investigated both in adult mice and during embryogenesis

Comparison of Nitrogen Incorporation in Tholins Produced by FUV Irradiation and Spark Discharge

The discovery of very heavy ions (Coates et al., 2007) in Titan's thermosphere has dramatically altered our understanding of the processes involved in the formation of the complex organic aerosols that comprise Titan's characteristic haze. Before Cassini's arrival, it was believed that aerosol production began in the stratosphere where the chemical processes were predominantly initiated by FUV radiation. This understanding guided the design of Titan atmosphere simulation experiments. However, the energy environment of the thermosphere is significantly different than the stratosphere; in particular there is a greater flux of EUV photons and energetic particles available to initiate chemical reactions, including the destruction of N2. in the upper atmosphere. Using a High Resolution Time-of-Flight Aerosol Mass Spectrometer (HR-ToF-AMS), we have obtained in situ composition measurements of aerosol particles (so'called "tholins") produced in CH4/N2 gas mixtures subjected to either FUV radiation (deuterium lamp, 115-400 nm) (Trainer et al., 2012) or a spark discharge. A comparison of the composition of tholins produced using the two different energy sources will be presented, in particular with regard to the variation in nitrogen content of the two types of tholin. Titan's aerosols are known to contain significant amounts of nitrogen (Israel et al., 2005) and therefore understanding the role of nitrogen in the aerosol chemistry is important to further our knowledge of the formation and evolution of aerosols in Titan's atmosphere

In situ measurement of atmospheric krypton and xenon on Mars with Mars Science Laboratory

Mars Science Laboratory's Sample Analysis at Mars (SAM) investigation has measured all of the stable isotopes of the heavy noble gases krypton and xenon in the martian atmosphere, in situ, from the Curiosity Rover at Gale Crater, Mars. Previous knowledge of martian atmospheric krypton and xenon isotope ratios has been based upon a combination of the Viking mission's krypton and xenon detections and measurements of noble gas isotope ratios in martian meteorites. However, the meteorite measurements reveal an impure mixture of atmospheric, mantle, and spallation contributions. The xenon and krypton isotopic measurements reported here include the complete set of stable isotopes, unmeasured by Viking. The new results generally agree with Mars meteorite measurements but also provide a unique opportunity to identify various non-atmospheric heavy noble gas components in the meteorites. Kr isotopic measurements define a solar-like atmospheric composition, but deviating from the solar wind pattern at 80Kr and 82Kr in a manner consistent with contributions originating from neutron capture in Br. The Xe measurements suggest an intriguing possibility that isotopes lighter than 132Xe have been enriched to varying degrees by spallation and neutron capture products degassed to the atmosphere from the regolith, and a model is constructed to explore this possibility. Such a spallation component, however, is not apparent in atmospheric Xe trapped in the glassy phases of martian meteorites

Laboratory Simulations of the Titan Surface to Elucidate the Huygens Probe GCMS Observations

The Cassini/Huygens mission has vastly increased the information we have available to stndy Satnro's moon Titan. The complete mission has included an array of observational methods including remote sensing techniques, upper atmosphere in-situ saropling, and the descent of the Huygens probe directly through the atmosphere to the surface [1,2]. The instruments on the Huygens probe remain the ouly source of in-situ measurements at the surface of Titan, and work evaluating these measurements to create a pict.rre of the surface environment is ongoing. In particular, the Gas Chromatograph Mass Spectrometer (GCMS) experiment on Huygens found that although there were no heavy hydrocarbons detected in the lower atmosphere, a rich spectrum of mass peaks arose once the probe landed on the surface [3,4], However, to date it has not been possible to extract the identity and abundances of the many minor components of the spectra due to a lack of temperatnre- and instrumentappropriate data for the relevant species. We are performing laboratory stndies designed to elucidate the spectrum collected on Titan's surface, utilizing a cryogenic charober maintained at appropriate temperature and pressure conditions. The experiments will simulate the temperatnre rise experienced by the surface, which led to an enhanced signal of volatiles detected by the Huygens GCMS. The objective of this study is to exaroine the characteristics of various surface analogs as measured by the Huygens GCMS flight spare instrument, which is currently housed in our laboratory at NASA Goddard Space Flight Center (GSFC). This identification cannot be adequately accomplished through theoretical work alone since the thermodynamic properties of many species at these temperatnres (94 K, HASI measurement [5]) are not known

Titan Mare Explorer (TiME): first in situ exploration of an extraterrestrial sea

The lakes and seas of Titan are a sink of products of photolysis in the atmosphere, and a crucial component in Titan's active methane cycle. In situ exploration of the seas is necessary to understand their intriguing prebiotic organic chemistry

Incidence, prevalence, and clinical course of hepatitis C following liver transplantation

Hepatitis C virus (HCV) is the agent responsible for posttransfusion hepatitis. The incidence, timing, and clinical course of HCV positive hepatitis in liver transplant recipients are unknown. Three hundred and seventeen donor-recipient liver transplant pairs were grouped on the basis of their pretransplant HCV antibody status. The biopsy findings were examined. Four distinct groups were identified on the basis of HCV serology: group I, both were negative; group II, donor was negative and recipient was positive; group III, donor was positive and recipient was negative; group IV, both were positive. The prevalence of anti-HCV positivity in recipients was 13.6%. The rate of seroconversion was 9.2%. Histologic hepatitis not ascribable to any specific cause other than non-A, non-B (NANB) hepatitis occurred in 13.8%. The incidence of histologic chronic active hepatitis was 1.6%, and none progressed to cirrhosis. The concordance rate for a positive anti-HCV serology and NANB hepatitis was 2.8%. Of the 35 patients (group II and IV) with positive anti-HCV serology pretransplant, only 17 were positive posttransplantation. Based on these data it can be concluded that posttransplant NANB hepatitis occurred in 13.8% of liver recipients. Twenty percent of these were anti-HCV positive. Progression to histologic chronic active hepatitis occurs over a period of 1-5 years in 1.6% of cases. © 1992

The glyoxal budget and its contribution to organic aerosol for Los Angeles, California, during CalNex 2010

Recent laboratory and field studies have indicated that glyoxal is a potentially large contributor to secondary organic aerosol mass. We present in situ glyoxal measurements acquired with a recently developed, high sensitivity spectroscopic instrument during the CalNex 2010 field campaign in Pasadena, California. We use three methods to quantify the production and loss of glyoxal in Los Angeles and its contribution to organic aerosol. First, we calculate the difference between steady state sources and sinks of glyoxal at the Pasadena site, assuming that the remainder is available for aerosol uptake. Second, we use the Master Chemical Mechanism to construct a two-dimensional model for gas-phase glyoxal chemistry in Los Angeles, assuming that the difference between the modeled and measured glyoxal concentration is available for aerosol uptake. Third, we examine the nighttime loss of glyoxal in the absence of its photochemical sources and sinks. Using these methods we constrain the glyoxal loss to aerosol to be 0-5 × 10-5 s-1 during clear days and (1 ± 0.3) × 10-5 s-1 at night. Between 07:00-15:00 local time, the diurnally averaged secondary organic aerosol mass increases from 3.2 μg m-3 to a maximum of 8.8 μg m -3. The constraints on the glyoxal budget from this analysis indicate that it contributes 0-0.2 μg m-3 or 0-4% of the secondary organic aerosol mass. Copyright 2011 by the American Geophysical Union