Nonsteroidal anti-inflammatory drugs (NSAIDs) are inhibitors of cyclooxygenase (COX). Our previous observations that celecoxib, a COX-2-specific inhibitor, not only inhibits rat mammary ...carcinogenesis, but also decreases fat deposition in rats fed a high-fat diet, prompted us to determine whether celecoxib affects lipid metabolism. At 57 days of age, two groups of 10 female Sprague Dawley rats were pair-fed a high-fat diet with or without 1500 ppm celecoxib for 15 weeks. Compared with controls, celecoxib-treated rats had 44.4% less hepatic triglycerides and 22.6% less intra-abdominal adipose tissue mass. In the liver and adipose tissue of several genes involved in fat metabolism and mobilization that we measured, only fatty acid synthase (FAS) was significantly down-regulated by celecoxib treatment. There were no differences in the level of prostaglandin E(2) in these tissues, indicating that celecoxib decreases fat accumulation by down-regulating FAS through a COX-2-independent mechanism. Among the potential molecular targets by which celecoxib may regulate FAS expression, only c-Jun N-terminal kinase-1 (JNK1) was significantly down-regulated. Furthermore, a known inhibitor of JNK suppressed FAS expression in rat hepatocytes. Our observations suggest that celecoxib suppresses FAS expression and decreases fat accumulation by down-regulating JNK1.
Melanoma differentiation associated gene-7/interleukin-24 (mda-7/IL-24) encodes a tumor suppressor gene implicated in the growth of various tumor types including breast cancer. We previously ...demonstrated that recombinant adenovirus-mediated mda-7/IL-24 expression in the mammary glands of carcinogen-treated (methylnitrosourea, MNU) rats suppressed mammary tumor development. Since most MNU-induced tumors in rats contain activating mutations in Ha-ras, which arenot frequently detected in humans, we presently examined the effect of MDA-7/IL-24 on Her2/Neu-induced mammary tumors, in which the RAS pathway is induced. We generated tet-inducible MDA-7/IL-24 transgenic mice and crossed them with Her2/Neu transgenic mice. Triple compound transgenic mice treated with doxycycline exhibited a strong inhibition of tumor development, demonstrating tumor suppressor activity by MDA-7/IL-24 in immune-competent mice. MDA-7/IL-24 induction also inhibited growth of tumors generated following injection of Her2/Neu tumor cells isolated from triple compound transgenic mice that had not been treated with doxycycline, into the mammary fat pads of isogenic FVB mice. Despite initial growth suppression, tumors in triple compound transgenic mice lost mda-7/IL-24 expression and grew, albeit after longer latency, indicating that continuous presence of this cytokine within tumor microenvironment is crucial to sustain tumor inhibitory activity. Mechanistically, MDA-7/IL-24 exerted its tumor suppression effect on HER2+ breast cancer cells, at least in part, through PERP, a member of PMP-22 family with growth arrest and apoptosis-inducing capacity. Overall, our results establish mda-7/IL-24 as a suppressor of mammary tumor development and provide a rationale for using this cytokine in the prevention/treatment of human breast cancer.
The New Zealand (NZ) lizard fossil record is currently limited to late Quaternary remains of modern taxa. The St Bathans Fauna (early Miocene, southern South Island) extends this record to 19-16 ...million years ago (Myr ago). Skull and postcranial elements are similar to extant Oligosoma (Lygosominae) skinks and Hoplodactylus (Diplodactylinae) geckos. There is no evidence of other squamate groups. These fossils, along with coeval sphenodontines, demonstrate a long conservative history for the NZ lepidosaurian fauna, provide new molecular clock calibrations and contradict inferences of a very recent (less than 8 Myr ago) arrival of skinks in NZ.
Melanoma differentiation-associated gene (MDA)-7)/interleukin (IL)-24, a member of the IL-10 family of cytokines, inhibits growth of various human cancer cells, yet the underlying mechanism is ...largely unknown. Here, we report that mda-7/IL-24 efficiently suppresses the development of rat mammary tumors in vivo. Microarray analysis for genes differentially expressed in rat mammary tumor cells overexpressing MDA-7/IL-24 compared with those that do not express this cytokine identified growth arrest-specific gene-3 (gas3) as a target for mda-7/IL-24. Upregulation of gas3 by mda-7/IL-24 was STAT3 dependent. Induction of gas3 inhibited attachment and proliferation of tumor cells in vitro and in vivo by inhibiting the interaction of β1 integrin with fibronectin. A mutated GAS3, which is unable to bind β1 integrin, was also unable to inhibit fibronectin-mediated attachment and cell growth both in adherent and suspension cultures, suggesting that GAS3 exerts its effects through interaction with and regulation of β1 integrin. Thus, mda-7/IL-24 inhibits breast cancer growth, at least in part, through upregulation of GAS3 and disruption of β1 integrin function. Importantly, the expression of the mda-7/IL-24 receptor, IL-20R1, is highly correlated with GAS3 expression in human breast cancer (P = 1.02 × 10(-9)), and the incidence of metastases is significantly reduced in patients with HER2(+) breast cancer expressing high-levels of IL-20R1. Together, our results identify a novel MDA-7/IL-24-GAS3-β1integrin-fibronectin signaling pathway that suppresses breast cancer growth and can be targeted for therapy.
Rich, T.H., Hopson, J.A., Gill, P.G., Trusler, P., Rogers-Davidson, S., Morton, S., Cifelli, R.L., Pickering, D., Kool, L., Siu, K., Burgmann, F.A., Senden, T., Evans, A.R., Wagstaff, B.E., ...Seegets-Villiers, D., Corfe, I.J., Flannery, T.F., Walker, K., Musser, A.M., Archer, M., Pian, R. & Vickers-Rich, P., June 2016. The mandible and dentition of the Early Cretaceous monotreme Teinolophos trusleri. Alcheringa 40, xx-xx. ISSN 0311-5518.
The monotreme Teinolophos trusleri Rich, Vickers-Rich, Constantine, Flannery, Kool & van Klaveren,
1999
from the Early Cretaceous of Australia is redescribed and reinterpreted here in light of additional specimens of that species and compared with the exquisitely preserved Early Cretaceous mammals from Liaoning Province, China. Together, this material indicates that although T. trusleri lacked a rod of postdentary bones contacting the dentary, as occurs in non-mammalian cynodonts and basal mammaliaforms, it did not share the condition present in all living mammals, including monotremes, of having the three auditory ossicles, which directly connect the tympanic membrane to the fenestra ovalis, being freely suspended within the middle ear cavity. Rather, T. trusleri appears to have had an intermediate condition, present in some Early Cretaceous mammals from Liaoning, in which the postdentary bones cum ear ossicles retained a connection to a persisting Meckel's cartilage although not to the dentary. Teinolophos thus indicates that the condition of freely suspended auditory ossicles was acquired independently in monotremes and therian mammals. Much of the anterior region of the lower jaw of Teinolophos is now known, along with an isolated upper ultimate premolar. The previously unknown anterior region of the jaw is elongated and delicate as in extant monotremes, but differs in having at least seven antemolar teeth, which are separated by distinct diastemata. The dental formula of the lower jaw of Teinolophos trusleri as now known is i2 c1 p4 m5. Both the deep lower jaw and the long-rooted upper premolar indicate that Teinolophos, unlike undoubted ornithorhynchids (including the extinct Obdurodon), lacked a bill.
Thomas H. Rich
trich@museum.vic.gov.au
, Sally Rogers-Davidson
srogers@museum.vic.gov.au
, David Pickering
dpick@museum.vic.gov.au
, Timothy F. Flannery
tim.flannery@textpublishing.com.au
, Ken Walker
kwalker@museum.vic.gov.au
, Museum Victoria, PO Box 666, Melbourne, Victoria 3001, Australia; James A. Hopson
jhopson@uchicago.edu
, Department of Organismal Biology & Anatomy, University of Chicago,1025 East 57th Street, Chicago, IL 60637, USA; Pamela G. Gill
pam.gill@bristol.ac.uk
, School of Earth Sciences, University of Bristol, Bristol BS8 1RJ, U.K. and Earth Science Department, The Natural History Museum, Cromwell Road, London SW7 5BD, UK; Peter Trusler
peter@petertrusler.com.au
, Lesley Kool
koollesley@gmail.com
, Doris Seegets-Villiers
doris.seegets-villiers@monash.edu
, Patricia Vickers-Rich
pat.rich@monash.edu
, School of Earth, Atmosphere and Environment, Monash University, Victoria 3800, Australia; Steve Morton
steve.morton@monash.edu
, Karen Siu
karen.siu@monash.edu
, School of Physics and Astronomy, Monash University, Victoria 3800, Australia; Richard L. Cifelli
rlc@ou.edu
Sam Noble Oklahoma Museum of Natural History, University of Oklahoma, Norman, OK 73072, USA; Flame A. Burgmann
flame.burgmann@monash.edu
, Monash Centre for Electron Microscopy, 10 Innovation Walk, Monash University, Clayton, Victoria 3800, Australia; Tim Senden
Tim.Senden@anu.edu.au
, Department of Applied Mathematics, Research School of Physical Sciences and Engineering, The Australian National University, Canberra, Australian Capital Territory 0200, Australia; Alistair R. Evans
alistair.evans@monash.edu
, School of Biological Sciences, Monash University, Victoria 3800, Australia; Barbara E. Wagstaff
wagstaff@unimelb.edu.au
, School of Earth Sciences, The University of Melbourne, Victoria 3010, Australia; Ian J. Corfe
ian.corfe@helsinki.fi
, Institute of Biotechnology, Viikinkaari 9, 00014, University of Helsinki, Finland; Anne M. Musser
anne.musser@austmus.gov.au
, Australian Museum, 1 College Street, Sydney NSW 2010 Australia; Michael Archer
m.archer@unsw.edu.au
, School of Biological, Earth, and Environmental Sciences, University of New South Wales, Sydney, NSW 2052, Australia; Rebecca Pian
rpian@amnh.org
, Division of Paleontology, American Museum of Natural History, Central Park West at 79th Street, New York, NY 10024-5192, USA. Received 7.4.2016; accepted 14.4.2016.
Protocols for the hormonal induction of ovulation and oviposition are essential tools for managing threatened amphibians with assisted reproduction, but responses vary greatly between species and ...even broad taxon groups. Consequently, it is necessary to assess effectiveness of such protocols in representative species when new taxa become targets for induction. The threatened genus Mixophyes (family Myobatrachidae) has amongst the highest proportion of endangered species of all the Australian amphibians. This study developed and optimised the induction of oviposition in a non-threatened member of this taxon, the great barred frog (Mixophyes fasciolatus).
Gravid female M. fasciolatus were induced to oviposit on one or more occasions by administration of human chorionic gonadotropin (hCG) with or without priming with pregnant mare serum gonadotropin (PMSG). Treatments involved variations in hormone doses and combinations (administered via injection into the dorsal lymph sacs), and timing of administration. Pituitary homogenates from an unrelated bufonid species (Rhinella marina) were also examined with hCG.
When injected alone, hCG (900 to 1400 IU) induced oviposition. However, priming with two time dependent doses of PMSG (50 IU, 25 IU) increased responses, with lower doses of hCG (200 IU). Priming increased response rates in females from around 30% (hCG alone) to more than 50% (p = 0.035), and up to 67%. Increasing the interval between the first PMSG dose and first hCG dose from 3 to 6 days also produced significant improvement (p<0.001). Heterologous pituitary extracts administered with hCG were no more effective than hCG alone (p = 0.628).
This study found that M. fasciolatus is amongst the few amphibian species (including Xenopus (Silurana) and some bufonids) that respond well to the induction of ovulation utilising mammalian gonadotropins (hCG). The optimal protocol for M. fasciolatus involved two priming doses of PMSG (50 IU and 25 IU) administered at 6 and 4 days respectively, prior to two doses of hCG (100 IU), 24 hours apart. This study is also the first to demonstrate in an amphibian species that responds to mammalian gonadotropins that an increase in the ovulation rate occurs after priming with a gonadotropin (PMSG) with FSH activity.
To report a technique for eye enucleation in standing sedated horses and to report outcome in 40 horses. Retrospective study. Horses (n=40) requiring eye enucleation. The eye was enucleated using a ...transpalpebral technique in 40 horses restrained in stocks and sedated. Anesthesia of orbital structures was provided by local nerve blocks and infiltration of the surgical site with local anesthetic solution. Affected eyes were successfully enucleated with the horse standing. Short-term complications included moderate swelling (5 horses) and wound discharge (1). Long-term complications were not observed. A diseased eye can be safely enucleated with a horse standing. Enucleating an equine eye in the standing position eliminates the risks and costs of general anesthesia.
The 40 years that have passed since the beginning of the ‘environmental revolution’ has seen a large increase in development of policies for the protection of environmental media and a recognition by ...the public of the importance of environmental quality. There has been a shift from policy in reaction to high profile events, then to control of releases to single environmental media, and to the present position of moving toward integrated management of all environmental media at present. This development has moved away from classical chemical risk assessment toward environmental holism, including recognition of the ecological value of these media. This work details how policy developments have taken place for air and water, with examples from the USA and EU, in order to compare this with policy development regarding soil. Soil, with quite different policy frameworks and distinct uses, understanding, and threats compared to other environmental media, is currently attracting attention regarding the need for its protection independent of use. Challenges for soil policy are identified and evaluated, and recommendations on how these challenges can be overcome are discussed with relevance to water and air protection policy.
PDF
