Equine papillomavirus type 2‐associated, carcinomatous lesions of the penis and laryngopharynx of an elderly Icelandic horse gelding

A 28‐year‐old Icelandic horse gelding was presented with a laryngopharyngeal squamous cell carcinoma. The gelding had been treated for penile carcinoma in situ with a partial phallectomy 2 years earlier. Polymerase chain reaction of tumour DNA and subsequent amplicon sequencing revealed that the equine papillomavirus type 2 E6 oncogene sequences of both lesions were identical. There is strong evidence that equine papillomavirus type 2 is causally associated with genital squamous cell carcinomas and precancerous lesions. Recent reports indicate that equine papillomavirus type 2 might also play an active role in the pathogenesis of approximately 20% of equine squamous cell carcinomas in the oronasal, pharyngeal and laryngeal regions. To the authors’ knowledge, this is the first report of a horse consecutively developing a penile carcinoma in situ and a laryngopharyngeal squamous cell carcinoma that were apparently induced by the same equine papillomavirus type 2 variant. Possible equine papillomavirus type 2 infection pathways in this horse and the importance of early detection of lesions are discussed in this context

Measurement of neutron capture on 48^{48}Ca at thermal and thermonuclear energies

At the Karlsruhe pulsed 3.75\,MV Van de Graaff accelerator the thermonuclear $^{48}$Ca(n,$\gamma$)$^{49}$Ca(8.72\,min) cross section was measured by the fast cyclic activation technique via the 3084.5\,keV $\gamma$-ray line of the $^{49}$Ca-decay. Samples of CaCO$_3$ enriched in $^{48}$Ca by 77.87\,\% were irradiated between two gold foils which served as capture standards. The capture cross-section was measured at the neutron energies 25, 151, 176, and 218\,keV, respectively. Additionally, the thermal capture cross-section was measured at the reactor BR1 in Mol, Belgium, via the prompt and decay $\gamma$-ray lines using the same target material. The $^{48}$Ca(n,$\gamma$)$^{49}$Ca cross-section in the thermonuclear and thermal energy range has been calculated using the direct-capture model combined with folding potentials. The potential strengths are adjusted to the scattering length and the binding energies of the final states in $^{49}$Ca. The small coherent elastic cross section of $^{48}$Ca+n is explained through the nuclear Ramsauer effect. Spectroscopic factors of $^{49}$Ca have been extracted from the thermal capture cross-section with better accuracy than from a recent (d,p) experiment. Within the uncertainties both results are in agreement. The non-resonant thermal and thermonuclear experimental data for this reaction can be reproduced using the direct-capture model. A possible interference with a resonant contribution is discussed. The neutron spectroscopic factors of $^{49}$Ca determined from shell-model calculations are compared with the values extracted from the experimental cross sections for $^{48}$Ca(d,p)$^{49}$Ca and $^{48}$Ca(n,$\gamma$)$^{49}$Ca.Comment: 15 pages (uses Revtex), 7 postscript figures (uses psfig), accepted for publication in PRC, uuencoded tex-files and postscript-files also available at ftp://is1.kph.tuwien.ac.at/pub/ohu/Ca.u

Oscillator Strengths and Damping Constants for Atomic Lines in the J and H Bands

We have built a line list in the near-infrared J and H bands (1.00-1.34, 1.49-1.80 um) by gathering a series of laboratory and computed line lists. Oscillator strengths and damping constants were computed or obtained by fitting the solar spectrum. The line list presented in this paper is, to our knowledge, the most complete one now available, and supersedes previous lists.Comment: Accepted, Astrophysical Journal Supplement, tentatively scheduled for the Sep. 1999 Vol. 124 #1 issue. Text and tables also available at http://www.iagusp.usp.br/~jorge

Improved Color-Temperature Relations and Bolometric Corrections for Cool Stars

We present new grids of colors and bolometric corrections for F-K stars having 4000 K < Teff < 6500 K, 0.0 < log g < 4.5 and -3.0 < [Fe/H] < 0.0. A companion paper extends these calculations into the M giant regime. Colors are tabulated for Johnson U-V and B-V; Cousins V-R and V-I; Johnson-Glass V-K, J-K and H-K; and CIT/CTIO V-K, J-K, H-K and CO. We have developed these color-temperature (CT) relations by convolving synthetic spectra with photometric filter-transmission-profiles. The synthetic spectra have been computed with the SSG spectral synthesis code using MARCS stellar atmosphere models as input. Both of these codes have been improved substantially, especially at low temperatures, through the incorporation of new opacity data. The resulting synthetic colors have been put onto the observational systems by applying color calibrations derived from models and photometry of field stars which have Teffs determined by the infrared-flux method. The color calibrations have zero points and slopes which change most of the original synthetic colors by less than 0.02 mag and 5%, respectively. The adopted Teff scale (Bell & Gustafsson 1989) is confirmed by the extraordinary agreement between the predicted and observed angular diameters of the field stars. We have also derived empirical CT relations from the field-star photometry. Except for the coolest dwarfs (Teff < 5000 K), our calibrated, solar-metallicity model colors are found to match these and other empirical relations quite well. Our calibrated, 4 Gyr, solar-metallicity isochrone also provides a good match to color-magnitude diagrams of M67. We regard this as evidence that our calibrated colors can be applied to many astrophysical problems, including modelling the integrated light of galaxies. (abridged)Comment: To appear in the March 2000 issue of the Astronomical Journal. 72 pages including 16 embedded postscript figures (one page each) and 6 embedded postscript tables (18 pages total

MUC4 activates HER2 signalling and enhances the motility of human ovarian cancer cells

The mucin MUC4 is a high molecular weight transmembrane glycoprotein. It consists of a mucin-type subunit (MUC4α) and a transmembrane growth factor-like subunit (MUC4β). The mucin MUC4 is overexpressed in many epithelial malignancies including ovarian cancer, suggesting a possible role in the pathogenesis of these cancers. In this study, we investigated the functional role of MUC4 in the human ovarian cancer cell line SKOV3. The mucin MUC4 was ectopically expressed by stable transfection, and its expression was examined by western blot and confocal microscopy analyses. The in vitro studies demonstrated an enhanced motility of MUC4-expressing SKOV3 cells compared with the vector-transfected cells. The mucin MUC4 expression was associated with apparent changes in actin organisation, leading to the formation of microspike, lammelopodia and filopodia-like cellular projections. An enhanced protein expression and activation of HER2, a receptor tyrosine kinase, was also seen, although no significant change was observed in HER-2 transcript levels in the MUC4-transfected SKOV3 cells. Reciprocal co-immunoprecipitation revealed an interaction of MUC4 with HER2. Further, the MUC4-overexpressing SKOV3 cells exhibited an increase in the phosphorylation of focal adhesion kinase (FAK), Akt and ERK, downstream effectors of HER2. Taken together, our findings demonstrate that MUC4 plays a role in ovarian cancer cell motility, in part, by altering actin arrangement and potentiating HER2 downstream signalling in these cells

Epidermal growth factor mediates detachment from and invasion through collagen I and Matrigel in Capan-1 pancreatic cancer cells

BACKGROUND: Pancreatic adenocarcinoma is a highly invasive neoplasm. Epidermal growth factor (EGF) and its receptor are over expressed in pancreatic cancer, and expression correlates with invasion and metastasis. We hypothesized that EGF receptor and integrin signalling pathways interact in mediating cellular adhesion and invasion in pancreatic cancer, and that invasiveness correlates temporally with detachment from extracellular matrix. METHODS: We tested this hypothesis by investigating the role of EGF in mediating adhesion to and invasion through collagen I and Matrigel in the metastatic pancreatic adenocarcinoma cell line Capan-1. Adhesion and invasion were measured using in vitro assays of fluorescently-labeled cells. Adhesion and invasion assays were also performed in the primary pancreatic adenocarcinoma cell line MIA PaCa-2. RESULTS: EGF inhibited adhesion to collagen I and Matrigel in Capan-1 cells. The loss of adhesion was reversed by AG825, an inhibitor of erbB2 receptor signalling and by wortmannin, a PI3K inhibitor, but not by the protein synthesis inhibitor cycloheximide. EGF stimulated invasion through collagen I and Matrigel at concentrations and time courses similar to those mediating detachment from these extracellular matrix components. Adhesion to collagen I was different in MIA PaCa-2 cells, with no significant change elicited following EGF treatment, whereas treatment with the EGF family member heregulin-alpha elicited a marked increase in adhesion. Invasion through Matrigel in response to EGF, however, was similar to that observed in Capan-1 cells. CONCLUSION: An inverse relationship exists between adhesion and invasion capabilities in Capan-1 cells but not in MIA PaCa-2 cells. EGF receptor signalling involving the erbB2 and PI3K pathways plays a role in mediating these events in Capan-1 cells

Identification of novel small molecules that inhibit STAT3-dependent transcription and function

Activation of Signal Transducer and Activator of Transcription 3 (STAT3) has been linked to several processes that are critical for oncogenic transformation, cancer progression, cancer cell proliferation, survival, drug resistance and metastasis. Inhibition of STAT3 signaling has shown a striking ability to inhibit cancer cell growth and therefore, STAT3 has become a promising target for anti-cancer drug development. The aim of this study was to identify novel inhibitors of STAT-dependent gene transcription. A cellular reporter-based system for monitoring STAT3 transcriptional activity was developed which was suitable for high-throughput screening (Z’ = 0,8). This system was used to screen a library of 28,000 compounds (the ENAMINE Drug-Like Diversity Set). Following counter-screenings and toxicity studies, we identified four hit compounds that were subjected to detailed biological characterization. Of the four hits, KI16 stood out as the most promising compound, inhibiting STAT3 phosphorylation and transcriptional activity in response to IL6 stimulation. In silico docking studies showed that KI16 had favorable interactions with the STAT3 SH2 domain, however, no inhibitory activity could be observed in the STAT3 fluorescence polarization assay. KI16 inhibited cell viability preferentially in STAT3-dependent cell lines. Taken together, using a targeted, cell-based approach, novel inhibitors of STAT-driven transcriptional activity were discovered which are interesting leads to pursue further for the development of anti-cancer therapeutic agents

Feline Leukemia Virus and Other Pathogens as Important Threats to the Survival of the Critically Endangered Iberian Lynx (Lynx pardinus)

BACKGROUND: The Iberian lynx (Lynx pardinus) is considered the most endangered felid species in the world. In order to save this species, the Spanish authorities implemented a captive breeding program recruiting lynxes from the wild. In this context, a retrospective survey on prevalence of selected feline pathogens in free-ranging lynxes was initiated. METHODOLOGY/ PRINCIPAL FINDINGS: We systematically analyzed the prevalence and importance of seven viral, one protozoan (Cytauxzoon felis), and several bacterial (e.g., hemotropic mycoplasma) infections in 77 of approximately 200 remaining free-ranging Iberian lynxes of the Doñana and Sierra Morena areas, in Southern Spain, between 2003 and 2007. With the exception of feline immunodeficiency virus (FIV), evidence of infection by all tested feline pathogens was found in Iberian lynxes. Fourteen lynxes were feline leukemia virus (FeLV) provirus-positive; eleven of these were antigenemic (FeLV p27 positive). All 14 animals tested negative for other viral infections. During a six-month period in 2007, six of the provirus-positive antigenemic lynxes died. Infection with FeLV but not with other infectious agents was associated with mortality (p<0.001). Sequencing of the FeLV surface glycoprotein gene revealed a common origin for ten of the eleven samples. The ten sequences were closely related to FeLV-A/61E, originally isolated from cats in the USA. Endogenous FeLV sequences were not detected. CONCLUSIONS/SIGNIFICANCE: It was concluded that the FeLV infection most likely originated from domestic cats invading the lynx's habitats. Data available regarding the time frame, co-infections, and outcome of FeLV-infections suggest that, in contrast to the domestic cat, the FeLV strain affecting the lynxes in 2007 is highly virulent to this species. Our data argue strongly for vaccination of lynxes and domestic cats in and around lynx's habitats in order to prevent further spread of the virus as well as reduction the domestic cat population if the lynx population is to be maintained

Differential Effects of Pravastatin and Simvastatin on the Growth of Tumor Cells from Different Organ Sites

3-hydroxy-3-methylglutaryl coenzyme A reductase (HMGCR) inhibitors, commonly known as statins, may possess cancer preventive and therapeutic properties. Statins are effective suppressors of cholesterol synthesis with a well-established risk-benefit ratio in cardiovascular disease prevention. Mechanistically, targeting HMGCR activity primarily influences cholesterol biosynthesis and prenylation of signaling proteins. Pravastatin is a hydrophilic statin that is selectively taken up by a sodium-independent organic anion transporter protein-1B1 (OATP1B1) exclusively expressed in liver. Simvastatin is a hydrophobic statin that enters cells by other mechanisms. Poorly-differentiated and well-differentiated cancer cell lines were selected from various tissues and examined for their response to these two statins. Simvastatin inhibited the growth of most tumor cell lines more effectively than pravastatin in a dose dependent manner. Poorly-differentiated cancer cells were generally more responsive to simvastatin than well-differentiated cancer cells, and the levels of HMGCR expression did not consistently correlate with response to statin treatment. Pravastatin had a significant effect on normal hepatocytes due to facilitated uptake and a lesser effect on prostate PC3 and colon Caco-2 cancer cells since the OATP1B1 mRNA and protein were only found in the normal liver and hepatocytes. The inhibition of cell growth was accompanied by distinct alterations in mitochondrial networks and dramatic changes in cellular morphology related to cofilin regulation and loss of p-caveolin. Both statins, hydrophilic pravastatin and hypdrophobic simvastatin caused redistribution of OATP1B1 and HMGCR to perinuclear sites. In conclusion, the specific chemical properties of different classes of statins dictate mechanistic properties which may be relevant when evaluating biological responses to statins