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Formation flying opens new perspectives in solar physics, and allow to conceive giant, externally-occulted coronagraphs using a two-component space system with the external occulter on one spacecraft and the optical instrument on the other spacecraft at a distance of hundred meters. ASPIICS (Association de Satellites Pour l'Imagerie et l'Interferometrie de la Couronne Solaire) is a mission proposed to ESA in the framework of its PROBA-3 demonstration program of formation flying which is presently in phase A. ASPIICS is a single coronagraph which will perform both high spatial resolution imaging of the solar corona as well as 2-dimensional spectroscopy of several emission lines from the coronal base out to 3 R(symbol) using an etalon Fabry-Perot interferometer. The selected lines will allow to address different coronal regions: the forbidden line of FeXIV at 530.285 nm (hot coronal matter), Fe IX/X at 637.4 nm (coronal holes), HeI at 587.6 nm (cold matter). An additional broad spectral channel will image the white light corona so as to derive electron densities. The classical design of an externally-occulted coronagraph is adapted to the formation flying configuration allowing the detection of the very inner corona as close as 0.01 R(symbol) from the solar limb.

17 pp.-- Final full-text version of the paper available at: http://dx.doi.org/10.1016/j.icarus.2006.09.023., The OSIRIS cameras on the Rosetta spacecraft observed Comet 9P/Tempel 1 from 5 days before to 10 days after it was hit by the Deep Impact projectile. The Narrow Angle Camera (NAC) monitored the cometary dust in 5 different filters. The Wide Angle Camera (WAC) observed through filters sensitive to emissions from OH, CN, Na, and OI together with the associated continuum. Before and after the impact the comet showed regular variations in intensity. The period of the brightness changes is consistent with the rotation period of Tempel 1. The overall brightness of Tempel 1 decreased by about 10% during the OSIRIS observations. The analysis of the impact ejecta shows that no new permanent coma structures were created by the impact. Most of the material moved with ~ 200 m/s. Much of it left the comet in the form of icy grains which sublimated and fragmented within the first hour after the impact. The light curve of the comet after the impact and the amount of material leaving the comet (4.5 - 9 x 10e6 of water ice and a presumably larger amount of dust) suggest that the impact ejecta were quickly accelerated by collisions with gas molecules. Therefore, the motion of the bulk of the ejecta cannot be described by ballistic trajectories, and the validity of determinations of the density and tensile strength of the nucleus of Tempel 1 with models using ballistic ejection of particles is uncertain., The OSIRIS imaging system on board Rosetta is managed by the Max-Planck-Institute for Solar System Research in Katlenburg-Lindau (Germany), thanks to an International collaboration between Germany, France, Italy, Spain, and Sweden. We acknowledge the funding of the national space agencies ASI, CNES, DLR, the Spanish Space Program (Ministerio de Educacion y Ciencia), SNSB and ESA. IRAF is distributed by the National Optical Astronomy Observatories, which is operated by the Association of Universities for Research in Astronomy, Inc. (AURA) under cooperative agreement with the National Science Foundation. We acknowledge JPL's Horizons online ephemeris generator for providing the comet's position and rate of motion during the observations. This research has made use of NASA's Astrophysics Data System.

We investigate the thermal evolution of comet 67P/Churyumov-Gerasimenko's subsurface in the Seth_01 region, where active pits have been observed by the ESA/Rosetta mission. Our simulations show that clathrate destabilization and amorphous ice crystallization can occur at depths corresponding to those of the observed pits in a timescale shorter than 67P/Churyumov-Gerasimenko's lifetime in the comet's activity zone in the inner solar system. Sublimation of crystalline ice down to such depths is possible only in the absence of a dust mantle, which requires the presence of dust grains in the matrix small enough to be dragged out by gas from the pores. Our results are consistent with both pits formation via sinkholes or subsequent to outbursts, the dominant process depending on the status of the subsurface porosity. A sealed dust mantle would favor episodic and disruptive outgassing as a result of an increasing gas pressure in the pores, while a high porosity should allow the formation of large voids in the subsurface due to the continuous escape of volatiles. We finally conclude that the subsurface of 67P/Churyumov-Gerasimenko is not uniform at a spatial scale of 100-200~m., Accepted for publication in The Astrophysical Journal Letters

The Rosetta mission of the European Space Agency has been orbiting the comet 67P/Churyumov-Gerasimenko (67P) since August 2014 and is now in its escort phase. A large complement of scientific experiments designed to complete the most detailed study of a comet ever attempted are onboard Rosetta. We present results for the photometric and spectrophotometric properties of the nucleus of 67P derived from the OSIRIS imaging system, which consists of a Wide Angle Camera (WAC) and a Narrow Angle Camera (NAC). The disk-averaged phase function of the nucleus of 67P shows a strong opposition surge with a G parameter value of -0.13$\pm$0.01 in the HG system formalism and an absolute magnitude $H_v(1,1,0)$ = 15.74$\pm$0.02 mag. The integrated spectrophotometry in 20 filters covering the 250-1000 nm wavelength range shows a red spectral behavior, without clear absorption bands except for a potential absorption centered at $\sim$ 290 nm that is possibly due to SO$_2$ ice. The nucleus shows strong phase reddening, with disk-averaged spectral slopes increasing from 11\%/(100 nm) to 16\%/(100 nm) in the 1.3$^{\circ}$--54$^{\circ}$ phase angle range. The geometric albedo of the comet is 6.5$\pm$0.2\% at 649 nm, with local variations of up to $\sim$ 16\% in the Hapi region. From the disk-resolved images we computed the spectral slope together with local spectrophotometry and identified three distinct groups of regions (blue, moderately red, and red). The Hapi region is the brightest, the bluest in term of spectral slope, and the most active surface on the comet. Local spectrophotometry shows an enhancement of the flux in the 700-750 nm that is associated with coma emissions., 18, pages, 14 figures, Astronomy and Astrophysics, in press

7 pp.-- Article published by EDP Sciences and available at http://www.aanda.org or http://dx.doi.org/10.1051/0004-6361:20066694.-- Table 2 is only available in electronic form at http://www.aanda.org., [Context] In 2004 asteroid (2867) Steins has been selected as a flyby target for the Rosetta mission. Determination of its spin period and the orientation of its rotation axis are essential for optimization of the flyby planning., [Aims] Measurement of the rotation period and light curve of asteroid (2867) Steins at a phase angle larger than achievable from ground based observations, providing a high quality data set to contribute to the determination of the orientation of the spin axis and of the pole direction., [Methods] On March 11, 2006, asteroid (2867) Steins was observed continuously for 24 h with the scientific camera system OSIRIS onboard Rosetta. The phase angle was 41.7 degrees, larger than the maximum phase angle of 30 degrees when Steins is observed from Earth. A total of 238 images, covering four rotation periods without interruption, were acquired., [Results] The light curve of (2867) Steins is double peaked with an amplitude of ≈0.23 mag. The rotation period is 6.052 ± 0.007 h. The continuous observations over four rotation periods exclude the possibility of period ambiguities. There is no indication of deviation from a principal axis rotation state. Assuming a slope parameter of G = 0.15, the absolute visual magnitude of Steins is 13.05 ± 0.03., The OSIRIS imaging system on board Rosetta is managed by the Max-Planck-Intitute for Solar System Research in Katlenburg-Lindau (Germany), thanks to an International collaboration between Germany, France, Italy, Spain, and Sweden. The support of the national funding agencies DLR, CNES, ASI, MEC, and SNSB is gratefully acknowledged. We acknowledge the work of the Rosetta Science Operations Centre at ESA/ESTEC and of the Rosetta Mission Operations Centre at ESA/ESOC who made these observations possible on short notation and operated the spacecraft. S.C.L. acknowledges support from the Leverhulme Trust. This research made use of JPL’s online ephemeris generator (HORIZONS).

We present a detailed review of the calibration of the LASCO C3 coronagraph on the SOHO satellite. Most of the calibration has been in place since early in the mission and has been utilized to varying degrees as required by specific analysis efforts. However, using observational data from the nearly decade-long database of LASCO images, we have re-evaluated and improved many aspects of the calibration. This includes the photometric calibration, vignetting function, geometric distortion, stray light, and exposure and observation times. Using this comprehensive set of corrections we have generated and made available a set of calibrated coronal images along with a set of periodic background images to ease the accessibility and use of the LASCO database.

Udgivelsesdato: August 9 In this paper we develop a new method for genotyping Affymetrix single nucleotide polymorphism (SNP) array. The method is based on (i) using multiple arrays at the same time to determine the genotypes and (ii) a model that relates intensities of individual SNPs to each other. The latter point allows us to annotate SNPs that have poor performance, either because of poor experimental conditions or because for one of the alleles the probes do not behave in a dose-response manner. Generally, our method agrees well with a method developed by Affymetrix. When both methods make a call they agree in 99.25% (using standard settings) of the cases, using a sample of 113 Affymetrix 10k SNP arrays. In the majority of cases where the two methods disagree, our method makes a genotype call, whereas the method by Affymetrix makes a no call, i.e. the genotype of the SNP is not determined. By visualization it is indicated that our method is likely to be correct in majority of these cases. In addition, we demonstrate that our method produces more SNPs that are in concordance with Hardy-Weinberg equilibrium than the method by Affymetrix. Finally, we have validated our method on HapMap data and shown that the performance of our method is comparable to other methods.

The SIde-Looking Coronagraph (SILC) is intented to be proposed as part of the payload of the Solar Orbiter mission of the European Space Agency. Solar Orbiter will follow elliptic orbits with a large range of heliocentric distance, from 0.21 to 0.6 AU, and will reach heliographic latitudes as high as 38°. Furthermore, the spacecraft will have an offset pointing capability so as to target any point of the solar disk. These characteristics, in addition to the severe thermal environment, are very restrictive for a coronagraph and lead us to propose an externally occulted coronagraph entirely protected from direct sunlight by remaining in the shadow of the spacecraft and looking sideways. The optical design follows the general principles of an externally occulted coronagraph adapted to the side-looking concept. Although SILC loses the full spatial coverage of the corona, it can observe the inner part of the corona (down to 1.5 solar radii) during the whole mission and compensate the off-pointing of the spacecraft. The optical and mechanical designs of SILC are presented in detail.

The OSIRIS cameras (optical, spectroscopic, and infrared remote imaging system) onboard the European Space Agency's Rosetta spacecraft observed comet 9P/Tempel 1 for 17 days continuously around the time of NASA's Deep Impact mission. The cyanide-to-water production ratio was slightly enhanced in the impact cloud, compared with that of normal comet activity. Dust particles were flowing outward in the coma at >160 meters per second, accelerated by the gas. The slope of the brightness increase showed a dip about 200 seconds after the impact. Dust Afρ values before and long after the impact confirm the slight decrease of cometary activity. The dust-to-water mass ratio was much larger than 1.

The LYOT (LYman Orbiting Telescope) solar mission (proposed for a CNES micro-satellite) is composed of a disk imager and a coronagraph, both working at Lyman-α (121.6 nm). The coronagraph is internally occulted and all-reflective with a field-of-view of 1.2 R up to 2.5 R and high spatial resolution (2 pixels) amounts to 5 arcsec. The optical design is driven by the requirement to use a superpolished spherical mirror to minimize the scattered light into the instrument. The LYOT mission will observe the Lyman-α corona at high cadence (1 image/5 minutes) over a period of two years.

Urothelial cell carcinoma of the bladder (UCC) is a common malignancy with the highest prevalence rates found in Europe and United States where it rate as the fifth and fourth most common malignancy respectively. Bladder cancer is divided into two clinically divergent groups, non-muscle invasive (NMIBC) and muscle invasive bladder tumors (MIBC) accounting at diagnosis for 75% and 25% respectively and necessitates very different treatments. NMIBC have recurrence rate of 50-70% and often requires lifelong surveillance, however the prognosis is relatively good. In contrast MIBC often progresses and develop systemic disease. The aim of this study was to identify genomic rearrangements producing fusion transcripts in bladder cancer. Translocations in coding regions are known to be associated with malignancy. Especially in liquid tumors translocations are frequent; however the increased throughput in sequencing now identifies translocation associated with many solid tumors. In this study we used next generation sequencing to annotate genomic rearrangements in paired bladder cancer tumors (>90% tumor cells) presenting as Ta tumors and progressed to T1 or T2. Tumors were sequenced to 40-50x whole genome read depth (blood to >50x) and 65 million paired end reads of whole transcriptome RNAseq. Combining DNA and RNAseq, genomic rearrangements leading to expressed fusion transcript were identified (nFUSE, McPherson AW et. al. Genome Res. 2012 Jun 28). Approximately 25% of the predicted fusions could be validated using Sanger sequencing of cDNA. Importantly more than 80% of the fusions were only present in one of the paired tumors and primarily in the advanced tumor. Most of the fusions were out of frame and created truncated proteins. Two examples are truncation of metastasis suppressor 1 (MTSS1) and polymerase beta (POLB) both frequently mutated in cancer. As an interesting example of in frame fusions we found CTNNBL1 (Beta-Catenin-Like Protein 1) to be fused to FAM110A (family with sequence similarity 110, member A). Importantly the fusion places the promoter of CTNNBL1 in front of FAM110A and because the reading frame is preserved it is likely that both the start codon of CTNNBL1 and FAM110A can serve as translation start giving rise to nearly identical proteins. Furthermore, expression analysis showed significant increase of FAM110A expression in the affected tumor pair sample. Little is known about the FAM110 gene family, however they are shown to localizes to centrosomes and spindle poles and could potentially play an essential role in chromosome segregation and thereby cancer development. All sequencing was performed on the Illumina HiSeq platform. Citation Format: Iver K. Nordentoft, Karin Birkenkamp-Demtroder, Philippe Lamy, Thomas Reinert, Søren Vang, Jakob Hedegaard, Kasper Thorsen, Lars Dyrskjøt, Jakob Skou Pedersen, Torben Falck Ørntoft. Genome and RNA sequencing identifies fusion transcripts in bladder cancer. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 3560. doi:10.1158/1538-7445.AM2014-3560

International audience; Context. Little is known about the internal structure of cometary nuclei. In addition to understanding their accretion in the early solar nebula and their subsequent evolution in the solar system, we find this question to be of acute and timely interest in the case of 67P/Churyumov-Gerasimenko (hereafter 67P/C-G) due to be visited by the Rosetta spacecraft in the second half of 2014. In particular, the successful landing of the Philae surface module depends critically upon the bulk density of the nucleus and the structure of its surface layer. Aims. In addition to fostering our general knowledge of these properties, it is important to exploit all possible information to assist in preparing the delivery of Philae. Methods. We performed an in-depth analysis of the observations done with the radar system of the Arecibo Observatory in November 1982 when comet 67P/C-G had a close encounter with Earth at a geocentric distance of 0.4 AU taking our present knowledge of the properties of its nucleus (size, rotational state) into account. Results. In the absence of a detectable radar echo, we determined a maximum radar cross section of 0.7 km(2), leading to a maximum radar albedo of 0.05. This low albedo probably results from a combination of a low radar reflectivity material and a lightly packed upper layer of the nucleus with substantial roughness (rms slope of approximate to 55 degrees), consistent with its low thermal inertia. Based on radar observations of other cometary nuclei and asteroids, it is unlikely that the albedo can be lower than 0.04 so that we were able to constrain the dielectric permittivity of the subsurface layer to a narrow range of 1.9 to 2.1. Laboratory measurements and our modeling of mixtures of ice and dust have led to a porosity in the range of approximately 55 to 65% and a density in the range of approximate to 600 approximate to 1000 kg m(-3) for the top approximate to 2.5 m layer of the nucleus. This would be the bulk density range for a homogeneous nucleus and would place the success of the landing at risk, but an inhomogeneous nucleus with an overall density below this range remains a possibility.

Summary: The use of high-density SNP arrays for investigating copy number alterations in clinical tumor samples, with intra tumor heterogeneity and varying degrees of normal cell contamination, imposes several problems for commonly used segmentation algorithms. This calls for flexibility when setting thresholds for calling gains and losses. In addition, sample normalization can induce artifacts in the copy-number ratios for the non-changed genomic elements in the tumor samples. Results: We present an open source R package, Rseg, which allows the user to define sample-specific thresholds to call gains and losses. It also allows the user to correct for normalization artifacts. Availability: The R package, Rseg, is available at: http://www.cs.au.dk/~plamy/Rseg/ and runs on Linux and MS-Windows. Contact: plamy@cs.au.dk Supplementary information: Supplementary data are available at Bioinformatics online.

International audience; The panoramic camera (PanCam) imaging experiment is designed to obtain high-resolution multispectral stereoscopic panoramic images from each of the four Mars NetLander 2005 sites. The main scientific objectives to be addressed by the PanCam experiment are (1) to locate the landing sites and support the NetLander network sciences, (2) to geologically investigate and map the landing sites, and (3) to study the properties of the atmosphere and of variable phenomena. To place in situ measurements at a landing site into a proper regional context, it is necessary to determine the lander orientation on ground and to exactly locate the position of the landing site with respect to the available cartographic database. This is not possible by tracking alone due to the lack of on-ground orientation and the so-called map-tie problem. Images as provided by the PanCam allow to determine accurate tilt and north directions for each lander and to identify the lander locations based on landmarks, which can also be recognized in appropriate orbiter imagery. With this information, it will be further possible to improve the Mars-wide geodetic control point network and the resulting geometric precision of global map products. The major geoscientific objectives of the PanCam lander images are the recognition of surface features like ripples, ridges and troughs, and the identification and characterization of different rock and surface units based on their morphology, distribution, spectral characteristics, and physical properties. The analysis of the PanCam imagery will finally result in the generation of precise map products for each of the landing sites. So far comparative geologic studies of the Martian surface are restricted to the timely separated Mars Pathfinder and the two Viking Lander Missions. Further lander missions are in preparation (Beagle-2, Mars Surveyor 03). NetLander provides the unique opportunity to nearly double the number of accessible landing site data by providing simultaneous and long-term observations at four different surface locations which becomes especially important for studies of variable surface features as well as properties and phenomena of the atmosphere. Major changes on the surface that can be detected by PanCam are caused by eolian activities and condensation processes, which directly reflect variations in the prevailing near-surface wind regime and the diurnal and seasonal volatile and dust cycles. Atmospheric studies will concentrate on the detection of clouds, measurements of the aerosol contents and the water vapor absorption at 936 nm. In order to meet these objectives, the proposed PanCam instrument is a highly miniaturized, dedicated stereo and multispectral imaging device. The camera consists of two identical camera cubes, which are arranged in a common housing at a fixed stereo base length of 11 cm. Each camera cube is equipped with a CCD frame transfer detector with 1024×1024 active pixels and optics with a focal length of 13 mm yielding a field-of-view of 53°×53° and an instantaneous filed of view of 1.1 mrad. A filter swivel with six positions provides different color band passes in the wavelength range of 400-950 nm. The camera head is mounted on top of a deployable scissors boom and can be rotated by 360° to obtain a full panorama, which is already covered by eight images. The boom raises the camera head to a final altitude of 90 cm above the surface. Most camera activities will take place within the first week and the first month of the mission. During the remainder of the mission, the camera will operate with a reduced data rate to monitor time-dependent variations on a daily basis. PanCam is a joint German/French project with contributions from DLR, Institute of Space Sensor Technology and Planetary Exploration, Berlin, Institut d'Astrophysique Spatiale, CNRS, Orsay, and Service d'Aéronomie, CNRS, Verrières-le-Buisson.

We report the properties of all the 841 coronal mass ejections (CMEs) observed by the Solar and Heliospheric Observatory (SOHO) Large Angle Spectroscopic Coronagraph (LASCO) C2 and C3 white-light coronagraphs from January 1996 through June 1998, and we compare those properties to previous observations by other similar instruments. Both the CME rate and the distribution of apparent locations of CMEs varied during this period as expected based on previous solar cycles. The distribution of apparent speeds and the fraction of CMEs showing acceleration were also in agreement with earlier reports. The pointing stability provided by an L-1 orbit and the use of CCD detectors have resulted in superior brightness sensitivity for LASCO over earlier coronagraphs; however, we have not detected a significant population of fainter (i.e., low mass) CMEs. The general shape of the distribution of apparent sizes for LASCO CMEs is similar to those of earlier reports, but the average (median) apparent size of 72° (50°) is significantly larger. The larger average apparent size is predominantly the result of the detection of a population of partial and complete halo CMEs, at least some of which appear to be events with a significant longitudinal component directed along the Sun-Earth line, either toward or away from the Earth. Using full disk solar images obtained by the Extreme ultraviolet Imaging Telescope (EIT) on SOHO, we found that 40 out of 92 of these events might have been directed toward the Earth, and we compared the timing of those with the Kp geomagnetic storm index in the days following the CME. Although the “false alarm” rate was high, we found that 15 out of 21 (71%) of the Kp ≥ 6 storms could be accounted for as SOHO LASCO/EIT frontside halo CMEs. If we eliminate three Kp storms that occurred following LASCO/EIT data gaps, then the possible association rate was 15 out of 18 (83%).

Applications have been received from Dr. Peter Wheatley (proposed by UK), Prof. Harald Schuh (proposed by Austria), and Dr. Busaba Kramer (proposed by Thailand). All applications were endorsed, with the caveat that Dr. Kramer's application needs to be endorsed by at least one of the other commissions since she has not a publication record in our field.

Two coronal mass ejections have been well observed by the LASCO coronagraphs to move out into the interplanetary medium as disconnected plasmoids. The first, on July 28, 1996, left the Sun above the west limb around 18:00 UT. As it moved out, a bright V-shaped structure was visible in the C2 coronagraph which moved into the field-of-view of C3 and could be observed out to beyond 28 solar radii. The derived average velocity in the plane of the sky was 110 ± 5 km s-1 out to 5 solar radii, and above 15 solar radii the velocity was 269 ± 10 km s-1. Thus there is evidence of some acceleration around 6 solar radii. The second event occurred on November 5, 1996 and left the west limb around 04:00 UT. The event had an average velocity in the plane of the sky of ∼54 km s-1 below 4 R, and it accelerated rapidly around 5 R up to 310 ± 10 km s-1. In both events the rising plasmoid is connected back to the Sun by a straight, bright ray, which is probably a signature of a neutral sheet. In the November event there is evidence for multiple plasmoid ejections. The acceleration of the plasmoids around a projected altitude of 5 solar radii is probably a manifestation of the source surface of the solar wind.

We report observations by the Large Angle Spectrometric Coronagraph (LASCO) on the SOHO spacecraft of three coronal green-line transients that could be clearly associated with coronal mass ejections (CMEs) detected in Thomson-scattered white light. Two of these events, with speeds >25 km s-1, may be classified as ‘whip-lite’ transients. They are associated with the core of the white-light CMEs, identified with erupting prominence material, rather than with the leading edge of the CMEs. The third green-line transient has a markedly different appearance and is more gradual than the other two, with a projected outward speed < 10 km s-1 . This event corresponds to the leading edge of a’ streamer blowout’ type of CME. A dark void is left behind in the emission-line corona following each of the fast eruptions. Both fast emission-line transients start off as a loop structure rising up from close to the solar surface. We suggest that the driving mechanism for these events may be the emergence of new bipolar magnetic regions on the surface of the Sun, which destabilize the ambient corona and cause an eruption. The possible relationship of these events to recent X-ray observations of CMEs is briefly discussed.

We present a qualitative and quantitative comparison of a single coronal mass ejection (CME) as observed by LASCO (My 28-29, 1996) with the results of a three-dimensional axisymmetric time-dependent magnetohydrodynamic model of a flux rope interacting with a helmet streamer. The particular CME considered was selected based on the appearance of a distinct ‘tear-drop’ shape visible in animations generated from both the data and the model.

Purpose: Diagnostic and prognostic tools for prostate cancer (PC) are suboptimal causing overtreatment of indolent PC and risk of delayed treatment of aggressive PC. Here, we identify six novel candidate DNA methylation markers for PC with promising diagnostic and prognostic potential. Methods: Microarray-based screening and bisulfite sequencing of 20 non-malignant and 29 PC tissue specimens were used to identify new candidate DNA hypermethylation markers for PC. Diagnostic and prognostic potential was evaluated in 35 formalin-fixed paraffin-embedded (FFPE) nonmalignant prostate tissue samples, 293 FFPE malignant radical prostatectomy (RP) samples (cohort 1), and 148 fresh-frozen malignant RP samples (cohort 2) collected in Denmark, Switzerland, Germany, and Finland. Sensitivity and specificity for PC was evaluated by receiver operating characteristic analyses. Correlations between DNA methylation levels and biochemical recurrence were assessed by log rank tests as well as uni- and multivariate cox regression analyses. A methylation-based prognostic model was developed in cohort 1 and validated in cohort 2. Results: Hypermethylation of AOX1, C1orf114, GAS6, HAPLN3, KLF8, and MOB3B was highly cancer-specific (AUCs 0.89-0.98). Furthermore, a three-gene methylation signature (AOX1/C1orf114/HAPLN3) was developed in cohort 1 and validated in cohort 2. High AOX1/C1orf114/HAPLN3 methylation was significantly associated with biochemical recurrence in multivariate analysis (P Citation Format: Christa Haldrup, Kamilla Mundbjerg, Else Marie Vestergaard, Philippe Lamy, Peter Wild, Wolfgang A. Schulz, Christian Arsov, Michael Borre Borre, Søren Høyer, Torben F. Ørntoft, Karina D. Sørensen. A three-gene DNA methylation signature for prediction of biochemical recurrence after radical prostatectomy of clinically localized prostate cancer. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 649. doi:10.1158/1538-7445.AM2013-649

Prostate cancer (PC) is the most common malignancy, and the second most common cause of cancer related death amongst men in the Western world. The PC biomarkers currently available are unable to distinguish between aggressive and indolent PC, causing significant over-diagnosis and over-treatment. Here, by genomewide profiling of the DNA methylome, we aimed to identify new molecular markers that can improve the accuracy of diagnosis and prognosis of PC. In total, 21 PC, 9 normal (N), and 12 adjacent normal (AN) prostate tissue samples, as well as 15 prostate (cancer) cell lines, were run on the Illumina Infinium HumanMethylation450 BeadChip, which investigates Identification of differential methylation between N and AN samples could potentially aid correct diagnosis of patients with false negative biopsies. However, only 16 probes showed significant differential methylation in N vs. AN samples (p-value We applied a Δβ cutoff value of 0.2 and a p-value of 0.05 (adjusted), which revealed 26,286 significantly differentially methylated CpG sites between PC and controls (3076 hypomethylated and 23,210 hypermethylated in PC). Global analysis showed that PC samples were hypermethylated in CpG islands (CGIs), a trend which was even more pronounced in CGI shores and shelves. Although less common overall, hypomethylation was also more prominent in shores and shelves compared to CGIs. Applying a strict Δβ cutoff value of 0.6, only 69 significantly differentially methylated CpG sites remained. Of these, 55 sites were gene associated (41 different genes), all were hypermethylated in PC samples, and all but one were located in CGIs. Out of these 41 genes, we selected 5 candidates for validation. In-house and publicly available gene expression datasets showed that at least three of the genes were downregulated in PC, consistent with silencing caused by aberrant promoter methylation. Initial validation was carried out in PC cell lines by bisulphite sequencing, which confirmed the array results for all 5 genes. We are currently validating these findings by methylation-specific qPCR analysis of a large independent patient cohort with long clinical follow-up, in order to assess the diagnostic/prognostic biomarker potential of these 5 novel candidate methylation markers. These results will be presented at the conference. Citation Format: Siri H. Strand, Michal Switnicki, Philippe Lamy, Soeren Hoeyer, Michael Borre, Jakob S. Pedersen, Torben Oerntoft, Karina D. Soerensen. Genome-wide profiling of the prostate cancer methylome for biomarker discovery. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 659. doi:10.1158/1538-7445.AM2013-659

Bladder cancer (BC) is a common malignancy with the highest incidence rates found in Europe and United States where it rates as the fifth and fourth most common malignancy, respectively. There are two clinically distinct groups of BC, non-muscle invasive (NMIBC) and muscle invasive bladder tumors (MIBC) accounting at diagnosis for 75% and 25%, respectively, and demanding very different treatments. NMIBC have the highest cancer recurrence rate observed (50-70%) and often necessitates lifelong surveillance, however the prognosis is relatively good. MIBC in contrast often progresses and develop systemic disease. To improve the treatment of BC it is essential to understand the disease biology and to be able to predict disease progression. In this study we applied the advance of next generation sequencing technology to annotate genomic mutations and genomic rearrangements to base pair resolution in four metachronous BC cases (>90% tumor cells) progressing from Ta to T1 or T2, and matching blood. Furthermore, we explored clonal relationship among the initial tumor and the progressing tumor. Each sample was sequenced to 40-50 x whole genome coverage, 200 x targeted Exome sequencing, and 65 million paired end reads of whole transcriptome RNA-seq. Eight normal urothelium biopsies from BPH patients were used as reference for the RNA-seq. Notably we identified genetic high impact alterations in KDMA6A, PIK3CA, ZNF233, FGFR3, UBE3C, TMEM128, HOXA11, HOXA2, ELF3, TP53, KAT2B and DYRK3 (corrected for background mutation rate). We annotated a total of 559 unique deletions, translocations, insertions and inversions. In total, 120 of these DNA breaks were selected for validation with PCR and Sanger sequencing (80% validation rate). Ingenuity pathway analysis identified 19 canonical pathways significantly affected in four out of 8 samples. Currently we are validating the SNV findings in 50 BC samples using Exome-Seq and RNA-seq. Furthermore, protein expression of selected genes are validated by immunohistochemistry on FFPE tissue sections from the discovery samples and on a tissue microarray containing 290 cores from Ta and T1 tumors in order to correlate protein expression to disease specific survival. All sequencing was performed on the Illumina HiSeq platform. The results reveal promising descriptive and potentially predictive knowledge that may help determine the genomic fingerprint facilitating progression of NMIBC to MIBC. Citation Format: Iver K. Nordentoft, Karin Birkenkamp-Demtroder, Philippe Lamy, Thomas Reinert, Niels Fristrup, Jakob Skou Pedersen, Søren Vang, Jakob Hedegaard, Kasper Thorsen, Michael Borre, Lars Dyrskjøt, Torben Falck Ørntoft. Whole genome and transcriptome analysis reveals novel genomic alterations in bladder cancer. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 3153. doi:10.1158/1538-7445.AM2013-3153

A STEREO mission concept requiring only a single new spacecraft has been proposed. The mission would place the new spacecraft in a heliocentric orbit and well off the Sun- Earth line, where it can simultaneously view both the solar source of heliospheric disturbances and their propagation through the heliosphere all the way to the earth. Joint observations, utilizing the new spacecraft and existing solar spacecraft in earth orbit or L1 orbit would provide a stereographic data set. The new and unique aspect of this mission lies in the vantage point of the new spacecraft, which is far enough from Sun-Earth line to allow an entirely new way of studying the structure of the solar corona, the heliosphere and solar-terrestrial interactions. The mission science objectives have been selected to take maximum advantage of this new vantage point. They fall into two classes: those possible with the new spacecraft alone and those possible with joint measurements using the new and existing spacecraft. The instrument complement on the new spacecraft supporting the mission science objectives includes a soft x-ray imager, a coronagraph and a sun-earth imager. Telemetry rate appears to be the main performance determinant. The spacecraft could be launched with the new Med-Lite system.

International audience; OBJECTIVE: To determine more precisely the clinical and biological characteristics of AIDS-related cholangitis, and to investigate prognostic variables of this disease. DESIGN: Retrospective clinical and prognostic study. SETTING: Biliary unit, Bicêtre Hospital, France. PATIENTS: HIV-positive patients (n = 52) referred to the unit between December 1986 and June 1993 for biliary symptoms leading to the suspicion of AIDS-related cholangitis, (42 men; 10 women; mean age, 37 +/- 8 years). INTERVENTION: Endoscopic retrograde cholangiopancreatography (ERCP) was performed in order to determine the cause of the biliary symptoms. MAIN OUTCOME MEASURE: Clinical features and evolution of the cholangitis. RESULTS: Among the 52 patients, 45 met the ERCP criteria of AIDS-related cholangitis (36 men; nine women). The diagnosis of cholangitis was strongly suggested by abdominal ultrasonography in 47% of the cases. ERCP showed papillary stenosis, diffuse cholangitis, extrahepatic cholangitis alone, and intrahepatic cholangitis alone in 60, 67, 7 and 27%, respectively. Endoscopic sphincterotomy was performed in 28 patients. Pain was relieved by sphincterotomy in nine patients, but the other clinical or biological features were not influenced. One-year and 2-year survival rates were 41 +/- 7% and 8 +/- 4%, respectively. Multidimensional analysis using a Cox model showed that a lymphocyte count > 500 x 10(6)/l was the only independent predictive factor of better survival. CONCLUSION: AIDS-related cholangitis is a disease which leads preferentially to papillary stenosis or diffuse abnormalities of the biliary tract. Prognostic factors depend on the stage of the HIV infection. Another diagnosis of cholestasis was found in approximately 15% of the patients who showed biliary symptoms.

The Large Angle Spectroscopic Coronagraph (LASCO) is a three coronagraph package which has been jointly developed for the Solar and Heliospheric Observatory (SOHO) mission by the Naval Research Laboratory (USA), the Laboratoire d’Astronomie Spatiale (France), the Max-Planck-Institut fur Aeronomie (Germany), and the University of Birmingham (UK). LASCO comprises three coronagraphs, C1, C2, and C3, that together image the solar corona from 1.1 to 30 R⊙ (C1: 1.1–3 R⊙, C2: 1.5–6 R⊙, and C3: 3.7 – 30 R⊙). The C1 coronagraph is a newly developed mirror version of the classic internally-occulted Lyot coronagraph, while the C2 and C3 coronagraphs are externally occulted instruments. High-resolution imaging spectroscopy of the corona from 1.1 to 3 R⊙ can be performed with the Fabry-Perot interferometer in C1. High-volume memories and a high-speed microprocessor enable extensive on-board image processing. Image compression by a factor of about 10 will result in the transmission of 10 full images per hour.

Colorectal cancer (CRC) is one of the leading causes of cancer death in Western countries. A significant number of CRC patients undergoing curative-intented surgery subsequently develop recurrence and die from the disease. MicroRNAs (miRNAs) are aberrantly expressed in cancers and appear to have both diagnostic and prognostic significance. In this study we identified novel miRNAs associated with recurrence of CRC. TaqMan® Human MicroRNA Array Set v2.0 was used to profile the expression of 667 miRNAs in 14 normal colon mucosas and 46 microsatellite stable CRC tumors. Four miRNAs (miR-362-3p, miR-570, miR-148a* and miR-944) were expressed at a lower level in the tumors from patients with recurrence (p < 0.015) compared to tumors from patients with no recurrence. A significant association of low expression with reduced disease free survival was confirmed for miR-362-3p in a second independent cohort of 43 CRC patients using single TaqMan® microRNA assays. In vitro functional analysis showed that over-expression of miR-362-3p in colon cancer cell lines (HCT116, LS174T, and DLD1) reduced cell viability and proliferation mainly due to cell cycle arrest. E2F1, USF2 and PTPN1 were identified as potential miR-362-3p targets by mRNA profiling of HCT116 cells over-expressing miR-362-3p. Subsequently, these genes were confirmed as direct targets by Luciferase reporter assays. In vitro knock-down confirmed that these targets are important players in the miR-362-3p target network. We conclude that miR-362-3p may be a novel prognostic marker in CRC and hypothesize that augmented expression of miR-362-3p may prevent the development of distant metastasis by targeting E2F1, USF2 and PTPN1. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 4138. doi:1538-7445.AM2012-4138

Carcinogenesis is paralleled by ongoing insults to tumor genome integrity, commonly sensed and reacted to by the DNA damage response (DDR). The DDR is thought to act as an inducible barrier against early tumor development, but, if compromised, may allow tumor progression and rampant genomic instability. However, the interplay between the DDR, genomic integrity, and tumor development is still poorly understood. To extend current knowledge of these issues, we analyzed 45 human bladder tumors from 22 patients using a combination of Affymetrix Genome-Wide Human SNP Arrays 6.0 and immunohistochemistry (IHC). This allowed us to characterize genomic aberrations at high resolution, and determine the tissue expression patterns of several DDR components in the context of the underlying genomic complexity. The complexity of individual SNP-profiles varied considerably and widespread aberrations included novel features such as 151 copy neutral loss of heterozygosity (LOH) regions. Some of these were of potential functional relevance because they spanned mutated FGFR3 and PIK3CA alleles, in addition to a homozygous deletion involving the p16 tumor suppressor locus at chr9p22. In fact, most (34/60) homozygous deletions identified were confined to this region. The SNP-profiles also showed that metachronous tumors generally had several aberrations in common, thus suggesting a clonal relationship. We partitioned tumor-derived SNP-profiles into three groups of increasing complexity, likely to reflect histories of varying genomic instability, and compared these to IHC results. DDR tissue staining patterns using phospho-specific antibodies against p53, γH2AX, ATR, and ATM, indicative of an activated DDR, were not correlated to the total sum of accumulated DNA damage. Rather, the most complex tumor genomes were associated with absence of p16 expression, a high Ki67-proliferation index, and abundant expression of the multifunctional DDR protein Timeless. Tipin, an important interaction partner of Timeless, was expressed without any association to Timeless staining patterns and genomic integrity. Interestingly, in a large cohort of more than 250 non-muscle invasive bladder tumors, Timeless expression was associated with risk of progression to muscle-invasive disease (p Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 3109. doi:1538-7445.AM2012-3109

Aberrant activation of the Wnt signaling pathway is causally involved in the formation of most colorectal cancers (CRCs). Whereas detailed knowledge exists regarding Wnt regulated protein coding genes, much less is known about the possible involvement of non-coding RNAs. Here we used TaqMan Array MicroRNA Cards, capable of detecting 664 unique human microRNAs (miRNAs), to describe changes of the miRNA transcriptome following disruption of beta-catenin/TCF4 activity in DLD1 CRC cells. Most miRNAs appeared to respond independently of host gene regulation and proximal TCF4 chromatin occupancy. A module of miRNAs suppressed by Wnt signaling in vitro was downregulated in a series of human primary CRCs (n = 46), and CRC cell lines (n = 7), relative to normal adjacent mucosa (n = 14). Several of these miRNAs (miR-145, miR-126, miR-30e-3p, and miR-139-5p) markedly inhibited CRC cell growth in vitro when ectopically expressed. By using an integrative approach of proteomics and microarrays, together interrogating thousands of proteins and genome-wide mRNA levels, we also provide detailed insight into the target gene network controlled by miR-30e-3p. Specifically HELZ and PIK3C2A were directly repressed via several functional seed matching binding motifs located within the transcripts. siRNA-mediated silencing of PIK3C2A partly phenocopied the growth suppressive phenotype of miR-30e-3p suggesting that miR-30e-3p restricts CRC cell growth in part by targeting PIK3C2A. Collectively, our study demonstrates that multiple miRNAs are upregulated as a consequence of forced attenuation of Wnt signaling in CRC cells, and some of these miRNAs inhibit cell growth, possibly through repression of several growth stimulatory cancer-related genes. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 3964. doi:10.1158/1538-7445.AM2011-3964

Cancer of the urinary bladder is one of the major cancers being the fifth most common neoplasm in the industrialised countries. Urothelial carcinomas account for more than 90% of all bladder cancers. The majority of bladder cancers are non-muscle invasive cancers characterized by frequent recurrences after resection and up to 25% will develop an aggressive phenotype. We investigated the methylation in bladder cancer with respect to location in genome, consistency, variation in metachronous tumors, impact on transcripts, chromosomal location, and usefulness as urinary markers of bladder cancer. In this study, a microarray assay with more than 27.000 CpG sites was utilized to analyze methylation in 56 samples. Independent validations were performed in 63 samples by methylation-sensitive high-resolution melting (MS-HRM) and bisulfite sequencing. Transcript levels were analyzed using expression microarrays, and pathways using dedicated software. DNA from 40 urinary specimens was analyzed by MS-HRM. Our results show that global methylation patterns were established within and outside CpG-islands. Differential methylation (p Our results suggest that both hypo- and hyper methylation is stage dependent, over-represented at chromosome 21, and has a restricted influence on transcript levels in general, but clearly on keratins. The methylated genes are highly promising urinary cancer markers. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 4801. doi:10.1158/1538-7445.AM2011-4801

Duodenal obstruction is a classic complication of Crohn's disease with duodenal involvement. However, malignant transformation of duodenal lesions has very rarely been reported, and diagnosis of such a transformation is rarely made preoperatively. We report the case of a 32-year-old patient with an 8-year history of Crohn's disease who underwent bypass gastrojejunostomy for a duodenal stricture. A year later, weight loss and biliary obstruction led to a further laparotomy. At operation, an advanced carcinoma with peritoneal seedings was confirmed. Of the three patients previously reported in the literature with duodenal cancer arising in Crohn's disease stricture, only one had a preoperative diagnosis of malignancy made from endoscopic biopsies. When considering the surgical bypass of Crohn's duodenal stricture, if preoperative endoscopy and biopsy cannot be performed on account of duodenal stricturing, we suggest performing a peroperative endoscopy via a jejunotomy in order to eliminate the diagnosis of associated duodenal malignancy.

Observations of Saturn's satellites and external rings during the 1980 edge-on presentation were obtained with a focal coronograph. A faint satellite traveling in the orbit of Dione and leading it by 72° has been detected, together with the two inner satellites already suspected (cf. J. W. Fountain and S. M. Larson, 1978, Icarus 36, 92–106). The external ring has been observed on both east and west sides; it may extend up to ⋍8.3 Saturn radii, and appears structured.

A comparison between two alternative scattering theories, the approximate method of depolarization factors and the exact Mie theory, is performed on a pure analytical basis for the case of spherical particles. It is shown that the usual assumption requiring that the radius be small compared with the interacting wavelength is insufficient to ensure the validity of the approximate method. The complete set of conditions are provided for both the scattered and absorbed fields.

A model of light scattering by large rough particles is proposed which is based on the high-energy approximation, the laws of geometrical optics and a mathematical description of the properties of the particles roughness. The calculated intensities and polarizations as functions of scattering angles agree well with experimental results except in the case of metallic particles.

Die Titelverbindungen 1a, b werden aus dem 24-Ketonen 5a, b durch Umsetzung mit Isopro-phenylmagnesiumbromid, Allylumlagerung mit Phosphortrijodid und Lithiumalanatreduktion einheitlich und in zufriedenstellender Ausbeute dargestellt. Eine rationelle Darstellung der Ausgangsketone wird beschrieben. The Synthesis of Stigmasta-5,24-dien-3β-ol und 5α-Stigmasta-7,24-dien-3β-ol The title compounds 1a,b are homogenous and in reasonable yield prepared from the 24-ketones 5a, b by reaction with isopropenyl magnesium bromide, allylic rearrangement with phosphorous triiodide and lithium aluminium hydride reduction. A rational preparation of the starting ketones is described.

A new heuristic derivation of the radiation pressure and Poynting-Robertson drag forces is presented for particles with general optical properties; previous derivations considered only perfectly absorbing materials. The equation of motion for a particle of mass m and geometrical cross-section A, moving with velocity v through a radiation field of energy flux F, is (to terms of order v/c)where r̂ is the radial unit vector, ṙ is the radial velocity, and c is the speed of light. The radiation pressure efficiency factor Qpr includes both scattering and absorption, it is evaluated using Mie theory for small spherical particles with measured optical properties that are irradiated by the actual solar spectrum. Very small particles (

Solar radiation forces on small particles in the solar system are examined, and the resulting orbital evolution of interplanetary and circumplanetary dust is considered. An expression is derived for the effects of radiation pressure and Poynting-Robertson drag on small, spherical particles using the energy and momentum transformation laws of special relativity, and numerical examples are presented to illustrate that radiation pressure and Poynting-Robertson drag are only important for particles within a narrow size range. The orbital consequences of these radiation forces are considered both for heliocentric and planetocentric orbiting particles, and the coupling between particle sizes and dynamics is discussed. A qualitative derivation is presented for the differential Doppler effect, which is due to the differential Doppler shifting of radiation from approaching and receding solar hemispheres, and the Yarkovsky effect, which is important for rotating meter-to kilometer-sized particles, is briefly described.

Five cases of epithelioid hemangioendothelioma of the liver are reported. This unusual type of vascular tumor is often difficult to diagnose; its angiogenic nature is not overt at the radiologic level and may be overlooked by conventional histologic examination. At imaging procedures, epithelioid hemangioendothelioma of the liver presents as multiple focal hypovascular areas, disseminated in both lobes. The combination of these imaging abnormalities with a peculiar set of demographic and clinical features, including young age, good general condition, and progressive course, is suggestive. However, the final diagnosis can be established only by histologic examination of appropriate material collected by guided liver biopsies and may be helped by immunohistochemistry and ultrastructural examination. The accurate diagnosis of epithelioid hemangioendothelioma of the liver is of clinical and therapeutic relevance. In view of its favorable clinical course, orthotopic liver transplantation may be considered for the treatment of this tumor when intrahepatic dissemination contraindicates partial hepatectomy and extrahepatic extension, excluded by exploratory laparotomy, is absent.

Near-normal incidence reflectance measurements in the interval 1026-1640 A were performed on four silicates already studied in the visible and infrared. A Kramers-Kronig analysis of these data is used to calculate the complex index of refraction m = n - ik. New transmission measurements improve the determination of k in the interval 2500-4500 A, except for andesite, which is more opaque than had been previously observed.

A geometrical approach, which differs from the classical Poinsot solution, is developed for the moment free motion of a rigid body in order to discuss the case when energy is dissipated internally. Conservation of angular momentum and conservation of energy are used, respectively, to construct two surfaces, a sphere S and an ellipsoid E, which always intersect along a closed curve C; some typical intersections are shown. The motion of the body is such that the lip of the angular momentum vector remains on a curve C. Although less complete than Poinsot solution, this geometrical description provides a check on some classical results and is particularly useful in characterizing the motion when the angular momentum is kept constant while the energy decreases; then the sphere S remains the same while the ellipsoid E shrinks. The final state, corresponding to the minimum possible energy configuration, is a pure rotation about the principal axis of maximum inertia. Many interesting problems (e.g., the rotational stability of artificial satellites, the axial alignment of asteroids, and the damping of the Chandler wobble for the Earth and pulsars) are discussed in the context of this solution.

COMET West has displayed some remarkable properties. Sekanina1 has studied the multiple splitting of its nucleus and also discussed the strange structure of its dust tail. This tail is characterised by a system of bright bands which do not correspond to the true synchronous band2 and which are shown by very few comets. We call these striae (striated tail) and to study them we have examined numerous original and duplicate pictures, and selected four observations (Table 1) which reveal that the morphology was relatively well conserved during the evolution of the dust tail over a period of more than 4 days. We have identified three striae (Fig. 1) which seem to propagate in space while retaining their basic form. This phenomenon is not unusual in plasmas, such as gas tails of comets3 or streamers in the solar K-corona4,5. However, this is apparently the first time that it has been observed in dust ‘clouds’. These striae, which we describe here, are made of dust grains which can be readily demonstrated by the wide-field colour photographs made by comet observers: the gas tail (type I) appears distinctly blue because of CN emission and is directly in the anti-solar direction as well as being well separated from the large dust tail (type II) which has a neutral colour.

A brief summary is given of the current concepts of the icy conglomerate cometary nucleus and of the origin of comets. Evidence that the cores of comets may contain less than average volatile material, wheter in formation or by radiative heating, raises the question of why at least two very faint short-period comets suddenly experienced violent outbursts (~4000 times in brightness). A preliminary study of close double comet nuclei as affected by differential nongravitational forces shows that a collision of a cometary satellite with its primary is a likely outcome. Thus double nuclei may possibly explain these rare but extreme outbrusts. Statistics suggest, however that most comet splitting and comet outbursts represent instrinsic activities in extremely non-homogeneous nuclei.