Cross-species gene expression analysis of species specific differences in the preclinical assessment of pharmaceutical compounds

Animals are frequently used as model systems for determination of safety and efficacy in pharmaceutical research and development. However, significant quantitative and qualitative differences exist between humans and the animal models used in research. This is as a result of genetic variation between human and the laboratory animal. Therefore the development of a system that would allow the assessment of all molecular differences between species after drug exposure would have a significant impact on drug evaluation for toxicity and efficacy. Here we describe a cross-species microarray methodology that identifies and selects orthologous probes after cross-species sequence comparison to develop an orthologous cross-species gene expression analysis tool. The assumptions made by the use of this orthologous gene expression strategy for cross-species extrapolation is that; conserved changes in gene expression equate to conserved pharmacodynamic endpoints. This assumption is supported by the fact that evolution and selection have maintained the structure and function of many biochemical pathways over time, resulting in the conservation of many important processes. We demonstrate this cross-species methodology by investigating species specific differences of the peroxisome proliferatoractivator receptor (PPAR) a response in rat and human

KELT-3b: A Hot Jupiter Transiting a V=9.8 Late-F Star

We report the discovery of KELT-3b, a moderately inflated transiting hot Jupiter with a mass of 1.477 (-0.067, +0.066) M_J, and radius of 1.345 +/- 0.072 R_J, with an orbital period of 2.7033904 +/- 0.000010 days. The host star, KELT-3, is a V=9.8 late F star with M_* = 1.278 (-0.061, +0.063) M_sun, R_* = 1.472 (-0.067, +0.065) R_sun, T_eff = 6306 (-49, +50) K, log(g) = 4.209 (-0.031, +0.033), and [Fe/H] = 0.044 (-0.082, +0.080), and has a likely proper motion companion. KELT-3b is the third transiting exoplanet discovered by the KELT survey, and is orbiting one of the 20 brightest known transiting planet host stars, making it a promising candidate for detailed characterization studies. Although we infer that KELT-3 is significantly evolved, a preliminary analysis of the stellar and orbital evolution of the system suggests that the planet has likely always received a level of incident flux above the empirically-identified threshold for radius inflation suggested by Demory & Seager (2011).Comment: 12 pages, 12 figures, accepted to Ap

Interactions between corticotropin releasing factor signaling and prophylactic antibiotics on measures of intestinal function in weaned and transported pigs

The study objective was to evaluate the interaction between corticotrophin releasing factor (CRF) receptor signaling and prophylactic antibiotic administration on intestinal physiology in newly weaned and transported pigs. Pigs (n = 56; 5.70 ± 1.05 kg) were weaned (20.49 ± 0.64 d), a blood sample was taken, and then pigs were given an intraperitoneal injection of saline (SAL; n = 28 pigs) or a CRF receptor antagonist (CRFA; n = 28 pigs; 30 μg/kg body weight; Astressin B), and then were transported in a livestock trailer for 12 h and 49 min. A second and third intraperitoneal injection was given at 4 h 42 min and 11 h 36 min into the transport process, respectively. Following transport, 4 SAL and 4 CRFA pigs were blood sampled and euthanized. The remaining 48 pigs were individually housed and given dietary antibiotics [AB; n = 12 SAL and 12 CRFA pigs; chlortetracycline (441 ppm) + tiamulin (38.6 ppm)] or no dietary antibiotics (NAB; n = 12 SAL and 12 CRFA pigs) for 14 d post-transport. Blood was collected at 12 h and on d 3, 7, and 14, and then pigs were euthanized on d 7 (n = 24) and d 14 (n = 24) post-weaning and transport. Circulating cortisol was reduced (p = 0.05) in CRFA pigs when compared to SAL pigs post-weaning and transport. On d 7, jejunal villus height and crypt depth was greater overall (p < 0.05) in AB-fed pigs versus NAB-fed pigs. On d 14, ileal crypt depth was reduced (p = 0.02) in CRFA pigs when compared to SAL pigs. Jejunal CRF mRNA abundance tended to be reduced (p = 0.09) on d 7 in CRFA pigs versus SAL pigs. On d 14, jejunal tumor necrosis factor-alpha was reduced (p = 0.01) in AB-fed pigs versus NAB-fed pigs. On d 7, change in glucose short-circuit current tended to be increased (p = 0.07) in CRFA pigs fed the AB diet when compared to CRFA pigs fed the NAB diet. In conclusion, CRFA pigs and pigs fed AB had some similar biological intestinal function measures post-weaning and transport

KELT-6b: A P~7.9 d Hot Saturn Transiting a Metal-Poor Star with a Long-Period Companion

We report the discovery of KELT-6b, a mildly-inflated Saturn-mass planet transiting a metal-poor host. The initial transit signal was identified in KELT-North survey data, and the planetary nature of the occulter was established using a combination of follow-up photometry, high-resolution imaging, high-resolution spectroscopy, and precise radial velocity measurements. The fiducial model from a global analysis including constraints from isochrones indicates that the V=10.38 host star (BD+31 2447) is a mildly evolved, late-F star with T_eff=6102 \pm 43 K, log(g_*)=4.07_{-0.07}^{+0.04} and [Fe/H]=-0.28 \pm 0.04, with an inferred mass M_*=1.09 \pm 0.04 M_sun and radius R_star=1.58_{-0.09}^{+0.16} R_sun. The planetary companion has mass M_P=0.43 \pm 0.05 M_J, radius R_P=1.19_{-0.08}^{+0.13} R_J, surface gravity log(g_P)=2.86_{-0.08}^{+0.06}, and density rho_P=0.31_{-0.08}^{+0.07} g~cm^{-3}. The planet is on an orbit with semimajor axis a=0.079 \pm 0.001 AU and eccentricity e=0.22_{-0.10}^{+0.12}, which is roughly consistent with circular, and has ephemeris of T_c(BJD_TDB)=2456347.79679 \pm 0.00036 and P=7.845631 \pm 0.000046 d. Equally plausible fits that employ empirical constraints on the host star parameters rather than isochrones yield a larger planet mass and radius by ~4-7%. KELT-6b has surface gravity and incident flux similar to HD209458b, but orbits a host that is more metal poor than HD209458 by ~0.3 dex. Thus, the KELT-6 system offers an opportunity to perform a comparative measurement of two similar planets in similar environments around stars of very different metallicities. The precise radial velocity data also reveal an acceleration indicative of a longer-period third body in the system, although the companion is not detected in Keck adaptive optics images.Comment: Published in AJ, 17 pages, 15 figures, 6 table

Ortervirales: A new viral order unifying five families of reverse-transcribing viruses

Reverse-transcribing viruses, which synthesize a copy of genomic DNA from an RNA template, are widespread in animals, plants, algae and fungi (1, 2).

KELT-6b: A P ~ 7.9 Day Hot Saturn Transiting a Metal-poor Star with a Long-period Companion

We report the discovery of KELT-6b, a mildly inflated Saturn-mass planet transiting a metal-poor host. The initial transit signal was identified in KELT-North survey data, and the planetary nature of the occulter was established using a combination of follow-up photometry, high-resolution imaging, high-resolution spectroscopy, and precise radial velocity measurements. The fiducial model from a global analysis including constraints from isochrones indicates that the V = 10.38 host star (BD+31 2447) is a mildly evolved, late-F star with T eff = 6102 ± 43 K, , and [Fe/H] = –0.28 ± 0.04, with an inferred mass M = 1.09 ± 0.04 M ☉ and radius . The planetary companion has mass MP = 0.43 ± 0.05 M Jup, radius , surface gravity , and density . The planet is on an orbit with semimajor axis a = 0.079 ± 0.001 AU and eccentricity , which is roughly consistent with circular, and has ephemeris of T c(BJDTDB) = 2456347.79679 ± 0.00036 and P = 7.845631 ± 0.000046 days. Equally plausible fits that employ empirical constraints on the host-star parameters rather than isochrones yield a larger planet mass and radius by ~4}-7}. KELT-6b has surface gravity and incident flux similar to HD 209458b, but orbits a host that is more metal poor than HD 209458 by ~0.3 dex. Thus, the KELT-6 system offers an opportunity to perform a comparative measurement of two similar planets in similar environments around stars of very different metallicities. The precise radial velocity data also reveal an acceleration indicative of a longer-period third body in the system, although the companion is not detected in Keck adaptive optics images

Resistance to paclitaxel in a cisplatin-resistant ovarian cancer cell line is mediated by P-glycoprotein

The IGROVCDDP cisplatin-resistant ovarian cancer cell line is also resistant to paclitaxel and models the resistance phenotype of relapsed ovarian cancer patients after first-line platinum/taxane chemotherapy. A TaqMan low-density array (TLDA) was used to characterise the expression of 380 genes associated with chemotherapy resistance in IGROVCDDP cells. Paclitaxel resistance in IGROVCDDP is mediated by gene and protein overexpression of P-glycoprotein and the protein is functionally active. Cisplatin resistance was not reversed by elacridar, confirming that cisplatin is not a P-glycoprotein substrate. Cisplatin resistance in IGROVCDDP is multifactorial and is mediated in part by the glutathione pathway and decreased accumulation of drug. Total cellular glutathione was not increased. However, the enzyme activity of GSR and GGT1 were up-regulated. The cellular localisation of copper transporter CTR1 changed from membrane associated in IGROV-1 to cytoplasmic in IGROVCDDP. This may mediate the previously reported accumulation defect. There was decreased expression of the sodium potassium pump (ATP1A), MRP1 and FBP which all have been previously associated with platinum accumulation defects in platinum-resistant cell lines. Cellular localisation of MRP1 was also altered in IGROVCDDP shifting basolaterally, compared to IGROV-1. BRCA1 was also up-regulated at the gene and protein level. The overexpression of P-glycoprotein in a resistant model developed with cisplatin is unusual. This demonstrates that P-glycoprotein can be up-regulated as a generalised stress response rather than as a specific response to a substrate. Mechanisms characterised in IGROVCDDP cells may be applicable to relapsed ovarian cancer patients treated with frontline platinum/taxane chemotherapy

Hypoxia and TGF-β Drive Breast Cancer Bone Metastases through Parallel Signaling Pathways in Tumor Cells and the Bone Microenvironment

BACKGROUND: Most patients with advanced breast cancer develop bone metastases, which cause pain, hypercalcemia, fractures, nerve compression and paralysis. Chemotherapy causes further bone loss, and bone-specific treatments are only palliative. Multiple tumor-secreted factors act on the bone microenvironment to drive a feed-forward cycle of tumor growth. Effective treatment requires inhibiting upstream regulators of groups of prometastatic factors. Two central regulators are hypoxia and transforming growth factor (TGF)- beta. We asked whether hypoxia (via HIF-1alpha) and TGF-beta signaling promote bone metastases independently or synergistically, and we tested molecular versus pharmacological inhibition strategies in an animal model. METHODOLOGY/PRINCIPAL FINDINGS: We analyzed interactions between HIF-1alpha and TGF-beta pathways in MDA-MB-231 breast cancer cells. Only vascular endothelial growth factor (VEGF) and the CXC chemokine receptor 4 (CXCR4), of 16 genes tested, were additively increased by both TGF-beta and hypoxia, with effects on the proximal promoters. We inhibited HIF-1alpha and TGF-beta pathways in tumor cells by shRNA and dominant negative receptor approaches. Inhibition of either pathway decreased bone metastasis, with no further effect of double blockade. We tested pharmacologic inhibitors of the pathways, which target both the tumor and the bone microenvironment. Unlike molecular blockade, combined drug treatment decreased bone metastases more than either alone, with effects on bone to decrease osteoclastic bone resorption and increase osteoblast activity, in addition to actions on tumor cells. CONCLUSIONS/SIGNIFICANCE: Hypoxia and TGF-beta signaling in parallel drive tumor bone metastases and regulate a common set of tumor genes. In contrast, small molecule inhibitors, by acting on both tumor cells and the bone microenvironment, additively decrease tumor burden, while improving skeletal quality. Our studies suggest that inhibitors of HIF-1alpha and TGF-beta may improve treatment of bone metastases and increase survival

Photonic hydrogel sensors

Analyte-sensitive hydrogels that incorporate optical structures have emerged as sensing platforms for point-of-care diagnostics. The optical properties of the hydrogel sensors can be rationally designed and fabricated through self-assembly, microfabrication or laser writing. The advantages of photonic hydrogel sensors over conventional assay formats include label-free, quantitative, reusable, and continuous measurement capability that can be integrated with equipment-free text or image display. This Review explains the operation principles of photonic hydrogel sensors, presents syntheses of stimuli-responsive polymers, and provides an overview of qualitative and quantitative readout technologies. Applications in clinical samples are discussed, and potential future directions are identified

Azimuthal anisotropy of charged jet production in root s(NN)=2.76 TeV Pb-Pb collisions

We present measurements of the azimuthal dependence of charged jet production in central and semi-central root s(NN) = 2.76 TeV Pb-Pb collisions with respect to the second harmonic event plane, quantified as nu(ch)(2) (jet). Jet finding is performed employing the anti-k(T) algorithm with a resolution parameter R = 0.2 using charged tracks from the ALICE tracking system. The contribution of the azimuthal anisotropy of the underlying event is taken into account event-by-event. The remaining (statistical) region-to-region fluctuations are removed on an ensemble basis by unfolding the jet spectra for different event plane orientations independently. Significant non-zero nu(ch)(2) (jet) is observed in semi-central collisions (30-50% centrality) for 20 <p(T)(ch) (jet) <90 GeV/c. The azimuthal dependence of the charged jet production is similar to the dependence observed for jets comprising both charged and neutral fragments, and compatible with measurements of the nu(2) of single charged particles at high p(T). Good agreement between the data and predictions from JEWEL, an event generator simulating parton shower evolution in the presence of a dense QCD medium, is found in semi-central collisions. (C) 2015 CERN for the benefit of the ALICE Collaboration. Published by Elsevier B.V. This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/).Peer reviewe