Localization of overexpressed c-myc mRNA in polycystic kidneys of the cpk mouse

Localization of overexpressed c-myc mRNA in polycystic kidneys of the cpk mouse. The C57BL/6J-cpk mouse has a form of autosomal-recessive polycystic kidney disease characterized by the rapid growth of large collecting duct cysts and the development of severe renal failure usually by three to four weeks of age. Previous studies had shown higher steady-state levels of proto-oncogene mRNA in these cystic kidneys. It is now shown using nuclear run-on transcription that the c-fos and c-myc proto-oncogenes are transcribed at higher rates in cystic kidneys, and thus that increased transcription, in part, may account for the increased mRNA levels. c-myc mRNA was detected by in situ hybridization in nephron anlagen and elongating tubules of normal and cystic kidneys during late fetal and early neonatal kidney development. Localization of c-myc expression in the normal kidney decreased with age over the three-week postnatal period. By contrast, c-myc mRNA was found in cysts as early as three days of age, with increased levels at two and three weeks, c-myc expression was also elevated in apparently normal, non-dividing proximal tubules in three-week-old cystic animals. On the basis of these findings, we suggest that c-myc expression is linked to the proliferation of cells engaged in the primary cystogenic process, and that expression of this gene in proximal tubule cells of severely azotemic animals reflects the compensatory response of residual tubular epithelial cells to progressive renal dysfunction

Targeting the vasopressin type-2 receptor for renal cell carcinoma therapy.

Arginine vasopressin (AVP) and its type-2 receptor (V2R) play an essential role in the regulation of salt and water homeostasis by the kidneys. V2R activation also stimulates proliferation of renal cell carcinoma (RCC) cell lines in vitro. The current studies investigated V2R expression and activity in human RCC tumors, and its role in RCC tumor growth. Examination of the cancer genome atlas (TCGA) database, and analysis of human RCC tumor tissue microarrays, cDNA arrays and tumor biopsy samples demonstrated V2R expression and activity in clear cell RCC (ccRCC). In vitro, V2R antagonists OPC31260 and Tolvaptan, or V2R gene silencing reduced wound closure and cell viability of 786-O and Caki-1 human ccRCC cell lines. Similarly in mouse xenograft models, Tolvaptan and OPC31260 decreased RCC tumor growth by reducing cell proliferation and angiogenesis, while increasing apoptosis. In contrast, the V2R agonist dDAVP significantly increased tumor growth. High intracellular cAMP levels and ERK1/2 activation were observed in human ccRCC tumors. In mouse tumors and Caki-1 cells, V2R agonists reduced cAMP and ERK1/2 activation, while dDAVP treatment had the reverse effect. V2R gene silencing in Caki-1 cells also reduced cAMP and ERK1/2 activation. These results provide novel evidence for a pathogenic role of V2R signaling in ccRCC, and suggest that inhibitors of the AVP-V2R pathway, including the FDA-approved drug Tolvaptan, could be utilized as novel ccRCC therapeutics

Transitional disks and their origins: an infrared spectroscopic survey of Orion A

Transitional disks are protoplanetary disks around young stars, with inner holes or gaps which are surrounded by optically thick outer, and often inner, disks. Here we present observations of 62 new transitional disks in the Orion A star-forming region. These were identified using the \textit{Spitzer Space Telescope}'s Infrared Spectrograph and followed up with determinations of stellar and accretion parameters using the Infrared Telescope Facility's SpeX. We combine these new observations with our previous results on transitional disks in Taurus, Chamaeleon I, Ophiuchus and Perseus, and with archival X-ray observations. This produces a sample of 105 transitional disks of "cluster" age 3 Myr or less, by far the largest hitherto assembled. We use this sample to search for trends between the radial structure in the disks and many other system properties, in order to place constraints on the possible origins of transitional disks. We see a clear progression of host star accretion rate and the different disk morphologies. We confirm that transitional disks with complete central clearings have median accretion rates an order of magnitude smaller than radially continuous disks of the same population. Pre-transitional disks --- those objects with gaps that separate inner and outer disks --- have median accretion rates intermediate between the two. Our results from the search for statistically significant trends, especially related to $\dot{M}$, strongly support that in both cases the gaps are far more likely to be due to the gravitational influence of Jovian planets or brown dwarfs orbiting within the gaps, than to any of the photoevaporative, turbulent or grain-growth processes that can lead to disk dissipation. We also find that the fraction of Class II YSOs which are transitional disks is large, 0.1-0.2, especially in the youngest associations.Comment: 96 pages, 25 figures, resubmitted to Ap

Global Gene Expression Profiling in PPAR-γ Agonist-Treated Kidneys in an Orthologous Rat Model of Human Autosomal Recessive Polycystic Kidney Disease

Kidneys are enlarged by aberrant proliferation of tubule epithelial cells leading to the formation of numerous cysts, nephron loss, and interstitial fibrosis in polycystic kidney disease (PKD). Pioglitazone (PIO), a PPAR-γ agonist, decreased cell proliferation, interstitial fibrosis, and inflammation, and ameliorated PKD progression in PCK rats (Am. J. Physiol.-Renal, 2011). To explore genetic mechanisms involved, changes in global gene expression were analyzed. By Gene Set Enrichment Analysis of 30655 genes, 13 of the top 20 downregulated gene ontology biological process gene sets and six of the top 20 curated gene set canonical pathways identified to be downregulated by PIOtreatment were related to cell cycle and proliferation, including EGF, PDGF and JNK pathways. Their relevant pathways were identified using the Kyoto Encyclopedia of Gene and Genomes database. Stearoyl-coenzyme A desaturase 1 is a key enzyme in fatty acid metabolism found in the top 5 genes downregulated by PIO treatment. Immunohistochemical analysis revealed that the gene product of this enzyme was highly expressed in PCK kidneys and decreased by PIO. These data show that PIO alters the expression of genes involved in cell cycle progression, cell proliferation, and fatty acid metabolism

Spitzer observations of the Orion OB1 association: second generation dust disks at 5-10 Myr

We report new Spitzer observations of intermediate mass stars in two regions of the Orion OB1 association located in the subassociations OB1a ($\sim$10 Myr) and OB1b ($\sim$5 Myr). In a representative sample of stars earlier than F5 of both stellar groups, we find a population of stars surrounded of debris disks, without excess in the IRAC bands and without emission lines in their optical spectra, but with a varying degree of 24{\micron} excess. Comparing our samples with 24{\micron} observations of intermediate mass stars in other stellar groups, spanning a range of ages from 2.5 Myr to 150 Myr, we find that debris disks are more frequent and have larger 24{\micron} excess at 10 Myr (OB1a). This trend agrees with predictions of models of evolution of solids in the outer regions of disks ($>$30 AU), where large icy objects ($\sim$1000 Km) begin to form at $\sim$10 Myr; the presence of these objects in the disk initiates a collisional cascade, producing enough dust particles to explain the relatively large 24 {\micron} excess observed in OB1a. The dust luminosity observed in the stellar groups older than 10 Myr declines roughly as predicted by collisional cascade models. Combining Spitzer observations, optical spectra and 2MASS data, we found a new Herbig Ae/Be star (HD290543) and a star (HD36444) with a large 24 {\micron} excess, both in OB1b. This last object could be explained as a intermediate stage between HAeBe and true debris systems or as a massive debris disk produced by a collision between two large objects ($>$1000 Km).Comment: 25 pages, 8 figures, 2 tables. To be published in Astrophysical Journal (Acepted: 24 Jul 2006

First Science Observations with SOFIA/FORCAST: Properties of Intermediate-Luminosity Protostars and Circumstellar Disks in OMC-2

We examine eight young stellar objects in the OMC-2 star forming region based on observations from the SOFIA/FORCAST early science phase, the Spitzer Space Telescope, the Herschel Space Observatory, 2MASS, APEX, and other results in the literature. We show the spectral energy distributions of these objects from near-infrared to millimeter wavelengths, and compare the SEDs with those of sheet collapse models of protostars and circumstellar disks. Four of the objects can be modelled as protostars with infalling envelopes, two as young stars surrounded by disks, and the remaining two objects have double-peaked SEDs. We model the double-peaked sources as binaries containing a young star with a disk and a protostar. The six most luminous sources are found in a dense group within a 0.15 x 0.25 pc region; these sources have luminosities ranging from 300 L_sun to 20 L_sun. The most embedded source (OMC-2 FIR 4) can be fit by a class 0 protostar model having a luminosity of ~50 L_sun and mass infall rate of ~10^-4 solar masses per year.Comment: Accepted by ApJ Letter

Magnetospheres and Disk Accretion in Herbig Ae/Be Stars

We present evidence of magnetically-mediated disk accretion in Herbig Ae/Be stars. Magnetospheric accretion models of Balmer and sodium profiles calculated with appropriate stellar and rotational parameters are in qualitative agreement with the observed profiles of the Herbig Ae star UX Ori, and yield a mass accretion rate of ~ 10^{-8} Msun/yr. If more recent indications of an extremely large rotation rate for this object are correct, the magnetic field geometry must deviate from that of a standard dipole in order to produce line emission consistent with observed flux levels. Models of the associated accretion shock qualitatively explain the observed distribution of excess fluxes in the Balmer discontinuity for a large ensemble of Herbig Ae/Be stars, and imply typically small mass accretion rates, < 10^{-7} Msun/yr. In order for accretion to proceed onto the star, significant amounts of gas must exist inside the dust destruction radius, which is potentially problematic for recently advocated scenarios of "puffed" inner dust wall geometries. However, our models of the inner gas disk show that for the typical accretion rates we have derived, the gas should be generally optically thin, thus allowing direct stellar irradiation of the inner dust edge of the disk.Comment: 32 pages, 12 figures, accepted by Ap

A One Health overview, facilitating advances in comparative medicine and translational research.

Table of contentsA1 One health advances and successes in comparative medicine and translational researchCheryl StroudA2 Dendritic cell-targeted gorilla adenoviral vector for cancer vaccination for canine melanomaIgor Dmitriev, Elena Kashentseva, Jeffrey N. Bryan, David T. CurielA3 Viroimmunotherapy for malignant melanoma in the companion dog modelJeffrey N. Bryan, David Curiel, Igor Dmitriev, Elena Kashentseva, Hans Rindt, Carol Reinero, Carolyn J. HenryA4 Of mice and men (and dogs!): development of a commercially licensed xenogeneic DNA vaccine for companion animals with malignant melanomaPhilip J. BergmanA5 Successful immunotherapy with a recombinant HER2-expressing Listeria monocytogenes in dogs with spontaneous osteosarcoma paves the way for advances in pediatric osteosarcomaNicola J. Mason, Josephine S. Gnanandarajah, Julie B. Engiles, Falon Gray, Danielle Laughlin, Anita Gaurnier-Hausser, Anu Wallecha, Margie Huebner, Yvonne PatersonA6 Human clinical development of ADXS-HER2Daniel O'ConnorA7 Leveraging use of data for both human and veterinary benefitLaura S. TremlA8 Biologic replacement of the knee: innovations and early clinical resultsJames P. StannardA9 Mizzou BioJoint Center: a translational success storyJames L. CookA10 University and industry translational partnership: from the lab to commercializationMarc JacobsA11 Beyond docking: an evolutionarily guided OneHealth approach to drug discoveryGerald J. Wyckoff, Lee Likins, Ubadah Sabbagh, Andrew SkaffA12 Challenges and opportunities for data applications in animal health: from precision medicine to precision husbandryAmado S. GuloyA13 A cloud-based programmable platform for healthHarlen D. HaysA14 Comparative oncology: One Health in actionAmy K. LeBlancA15 Companion animal diseases bridge the translational gap for human neurodegenerative diseaseJoan R. Coates, Martin L. Katz, Leslie A. Lyons, Gayle C. Johnson, Gary S. Johnson, Dennis P. O'BrienA16 Duchenne muscular dystrophy gene therapyDongsheng DuanA17 Polycystic kidney disease: cellular mechanisms to emerging therapiesJames P. CalvetA18 The domestic cat as a large animal model for polycystic kidney diseaseLeslie A. Lyons, Barbara GandolfiA19 The support of basic and clinical research by the Polycystic Kidney Disease FoundationDavid A. BaronA20 Using naturally occurring large animal models of human disease to enable clinical translation: treatment of arthritis using autologous stromal vascular fraction in dogsMark L. WeissA21 Regulatory requirements regarding clinical use of human cells, tissues, and tissue-based productsDebra A. WebsterA22 Regenerative medicine approaches to Type 1 diabetes treatmentFrancis N. KaranuA23 The zoobiquity of canine diabetes mellitus, man's best friend is a friend indeed-islet transplantationEdward J. RobbA24 One Medicine: a development model for cellular therapy of diabetesRobert J. Harman

Accretion in Young Stellar/Substellar Objects

We present a study of accretion in a sample of 45 young, low mass objects in a variety of star forming regions and young associations, about half of which are likely substellar. Based primarily on the presence of broad, asymmetric Halpha emission, we have identified 13 objects (~30% of our sample) which are strong candidates for ongoing accretion. At least 3 of these are substellar. We do not detect significant continuum veiling in most of the accretors with late spectral types (M5-M7). Accretion shock models show that lack of measurable veiling allows us to place an upper limit to the mass accretion rates of <~ 10^{-10} Msun/yr. Using magnetospheric accretion models with appropriate (sub)stellar parameters, we can successfully explain the accretor Halpha emission line profiles, and derive quantitative estimates of accretion rates in the range 10^{-12} < Mdot < 10^{-9} Msun/yr. There is a clear trend of decreasing accretion rate with stellar mass, with mean accretion rates declining by 3-4 orders of magnitude over ~ 1 - 0.05 Msun.Comment: 38 pages, including 8 figures and 6 tables, accepted by Ap