Sutherland W.J.,University of Cambridge |
Clout M.,University of Auckland |
Cote I.M.,Simon Fraser University |
Daszak P.,Wildlife Trust |
And 19 more authors.
Trends in Ecology and Evolution | Year: 2010
Horizon scanning identifies emerging issues in a given field sufficiently early to conduct research to inform policy and practice. Our group of horizon scanners, including academics and researchers, convened to identify fifteen nascent issues that could affect the conservation of biological diversity. These include the impacts of and potential human responses to climate change, novel biological and digital technologies, novel pollutants and invasive species. We expect to repeat this process and collation annually. © 2009 Elsevier Ltd. All rights reserved.
News Article | March 3, 2017
Donald Trump recently signed an executive order “Enhancing Public Safety in the Interior of the United States” stating, in part, that the Secretary of Homeland Security shall prioritize for removal those aliens described by the Congress as well as removable aliens who have been convicted of any criminal offense; have been charged with any criminal offense, where such charge has not been resolved; have committed acts that constitute a chargeable criminal offense; have engaged in fraud or willful misrepresentation in connection with any official matter or application before a governmental agency; have abused any program related to receipt of public benefits; are subject to a final order of removal, but who have not complied with their legal obligation to depart the United States; or, in the judgment of an immigration officer, otherwise pose a risk to public safety or national security. “These executive actions can potentially strip refugees and Lawful Permanent Residents of their statutory and constitutional rights,” said immigration attorney Carlos Navarro, of Heier, Ishola & Navarro. “Basically, this means that the immigration enforcement priorities have been broadened to absurd proportions where even people who are merely accused of a crime can be prioritized for removal.” In light of Trump’s executive order, Navarro lists the following three tips for immigrants who are facing removal: No. 1: Know your rights. “For many, this means seeking out an attorney that you trust and have them ready as a backup plan,” stressed Navarro. No. 2: Have an emergency plan with family. “This entails knowing what to do if one or both parents don’t come home,” noted Navarro. “Have a list of contact numbers and money set aside. Have a plan of where children should go if something like that should happen.” No. 3: Use preventative measures. It is imperative to always follow the law. “This means avoiding any interactions with law enforcement where you are the subject of investigation, but one should not be afraid of reporting crimes or cooperating with police,” concluded Navarro. About Carlos Navarro, Heier, Ishola & Navarro, PLLC Attorney Carlos Navarro, the son of two immigrants from Jalisco, Mexico, has a lifelong interest in United States’ immigration policies and a desire to help individuals who, like his family, seek peaceful and productive lives in the United States. Heier, Ishola & Navarro, PLLC, focuses on immigration, including deportation defense/appeals, bonds, stays of removal, asylum (affirmative or defensive), consular processing, waivers, DACA (Deferred Action), family/finance petitions, adjustment of status/visas, naturalization and federal criminal re-entry charges. For more information, please call (801) 886-0500, or visit http://hinlegal.com/. The law office is located at 1750 W. Research Way, Suite 204, West Valley City, UT 84119. About the NALA™ The NALA offers small and medium-sized businesses effective ways to reach customers through new media. As a single-agency source, the NALA helps businesses flourish in their local community. The NALA’s mission is to promote a business’ relevant and newsworthy events and achievements, both online and through traditional media. For media inquiries, please call 805.650.6121, ext. 361.
Chambers N.,University of Manchester |
Sheaff R.,University of Plymouth |
Mahon A.,University of Manchester |
Byng R.,Research Way |
And 4 more authors.
BMC Health Services Research | Year: 2013
Background: The direction of health service policy in England is for more diversification in the design, commissioning and provision of health care services. The case study which is the subject of this paper was selected specifically because of the partnering with a private sector organisation to manage whole system redesign of primary care and to support the commissioning of services for people with long term conditions at risk of unplanned hospital admissions and associated service provision activities. The case study forms part of a larger Department of Health funded project on the practice of commissioning which aims to find the best means of achieving a balance between monitoring and control on the one hand, and flexibility and innovation on the other, and to find out what modes of commissioning are most effective in different circumstances and for different services. Methods. A single case study method was adopted to explore multiple perspectives of the complexities and uniqueness of a public-private partnership referred to as the "Livewell project". 10 single depth interviews were carried out with key informants across the GP practices, the PCT and the private provider involved in the initiative. Results: The main themes arising from single depth interviews with the case study participants include a particular understanding about the concept of commissioning in the context of primary care, ambitions for primary care redesign, the importance of key roles and strong relationships, issues around the adoption and spread of innovation, and the impact of the current changes to commissioning arrangements. The findings identified a close and high trust relationship between GPs (the commissioners) and the private commissioning support and provider firm. The antecedents to the contract for the project being signed indicated the importance of leveraging external contacts and influence (resource dependency theory). Conclusions: The study has surfaced issues around innovation adoption in the healthcare context. The case identifies 'negotiated order', managerial performance of providers and disciplinary control as three media of power used in combination by commissioners. The case lends support for stewardship and resource dependency governance theories as explanations of the underpinning conditions for effective commissioning in certain circumstances within a quasi marketised healthcare system. © 2013 Chambers et al; licensee BioMed Central Ltd.
Ammoun S.,Research Way |
Schmid M.C.,Research Way |
Zhou L.,Research Way |
Ristic N.,Research Way |
And 4 more authors.
Oncogene | Year: 2012
Merlin is a tumour suppressor involved in the development of a variety of tumours including mesotheliomas. Neurofibromatosis type 2 (NF2), a dominantly inherited tumour disease, is also caused by loss of merlin. NF2 patients suffer from multiple genetically well-defined tumours, schwannomas are most frequent among those. Using our in vitro model for human schwannoma, we found that schwannoma cells display enhanced proliferation because of the overexpression/activation of platelet-derived growth factor receptor and ErbB2/3, increased cell-matrix adhesion because of the overexpression of integrins, and decreased apoptosis. Mechanisms underlying schwannomas basal proliferation and cell-matrix adhesion are not understood. Here, we investigated insulin-like growth factor-binding protein-1 (IGFBP-1), which is expressed and released from central nervous system tumours and strongly overexpressed in schwannoma at the mRNA level. IGFBP-1 acts via β1-integrin and focal-adhesion-kinase (FAK), which are strongly overexpressed and basally activated in schwannoma. Using short hairpin RNA knockdown, small inhibitors and recombinant IGFBP-1, we demonstrate that schwannoma cells, in contrast to Schwann cells, release IGFBP-1 that activates the Src/FAK pathway, via integrin β1, potentiating schwannoma's proliferation and cell-matrix adhesion. We show that FAK localizes to the nucleus and Src triggers IGFBP-1 production. Further, we observed downregulation of the tumour-suppressor phosphatase and tensin homolog in schwannoma cells leading to increased activity of anti-apoptotic AKT. Thus, IGFBP-1/integrin β1/Src/FAK pathway has a crucial role in merlin-related tumourigenesis and therefore represents an important therapeutic target in the treatment of merlin-deficient tumours. © 2012 Macmillan Publishers Limited All rights reserved.
Ammoun S.,Research Way |
Schmid M.C.,Research Way |
Triner J.,Research Way |
Manley P.,Novartis |
Hanemann C.O.,Research Way
Neuro-Oncology | Year: 2011
Loss of the tumor suppressor merlin is a cause of frequent tumors of the nervous system, such as schwannomas, meningiomas, and ependymomas, which occur spontaneously or as part of neurofibromatosis type 2 (NF2). Because there is medical need for drug therapies for these tumors, our aim is to find therapeutic targets. We have studied the pathobiology of schwannomas, because they are the most common merlin-deficient tumors and are a model for all merlin-deficient tumors. With use of a human schwannoma in vitro model, we previously described strong overexpression/activation of platelet-derived growth factor receptor-ß (PDGFR-b) leading to strong, long-lasting activation of extracellularsignal- regulated kinase (ERK1/2) and AKT and increased schwannoma growth, which we successfully inhibited using the PDGFR/Raf inhibitor sorafenib. However, the benign character of schwannomas may require long-term treatment; thus, drug tolerability is an issue. With the use of Western blotting, proliferation assays, viability assays, and a primary human schwannoma cell in vitro model, we tested the PDGFR/c-KIT inhibitors imatinib (Glivec; Novartis) and nilotinib (Tasigna; Novartis). Imatinib and nilotinib inhibited PDGF-DD-mediated ERK1/2 activation, basal and PDGF-DD-mediated activation of PDGFR-ß and AKT, and schwannoma proliferation. Nilotinib is more potent than imatinib, exerting its maximal inhibitory effect at concentrations lower than steady-state trough plasma levels. In addition, nilotinib combined with the MEK1/2 inhibitor selumetinib (AZD6244) at low concentrations displayed stronger efficiency toward tumor growth inhibition, compared with nilotinib alone. We suggest that therapy with nilotinib or combinational therapy that simultaneously inhibits PDGFR and the downstream Raf/MEK1/2/ERK1/2 pathway could represent an effective treatment for schwannomas and other merlin-deficient tumors. © The Author(s) 2011.
Reilly J.M.,University College London |
Reilly J.M.,Astrazeneca |
Dharmalingam B.,University College London |
Dharmalingam B.,University of Liverpool |
And 6 more authors.
Experimental Neurology | Year: 2016
Complex regional pain syndrome (CRPS) is thought to have an auto-immune component. One such target recently proposed from the effects of auto-immune IgGs on Ca2+ transients in cardiac myocytes and cell lines is the α1-adrenoceptor. We have tested whether such IgGs exerted comparable effects on nociceptive sensory neurons isolated from rat dorsal root ganglia. Depolarisation-induced [Ca2+]i transients were generated by applying 30 mM KCl for 2min and monitored by Fura-2 fluorescence imaging. No IgGs tested (including 3 from CRPS patients) had any significant effect on these [Ca2+]i transients. However, IgG from one CRPS patient consistently and significantly reduced the K+-induced response of cells that had been pre-incubated for 24 h with a mixture of inflammatory mediators (1 μM histamine, 5-hydroxytryptamine, bradykinin and PGE2). Since this pre-incubation also appeared to induce a comparable inhibitory response to the α1-agonist phenylephrine, this is compatible with the α1-adrenoceptor as a target for CRPS auto-immunity. A mechanism whereby this might enhance pain is suggested. © 2015.
Ammoun S.,University of Plymouth |
Cunliffe C.H.,New York University |
Allen J.C.,New York University |
Chiriboga L.,New York University |
And 5 more authors.
Neuro-Oncology | Year: 2010
Vestibular schwannomas (VS) arising sporadically or in patients with neurofibromatosis type 2 (NF2) consistently lack expression of Merlin, a tumor suppressor. Conventional treatment options include surgery and radiotherapy but there is no validated medical option. Recent evidence suggests that Merlin deficiency may result in abnormal activation of receptor tyrosine kinases (RTKs) and downstream signaling, promoting tumor growth. Although small-molecule RTK inhibitors are widely available for clinical use, no such therapy has been validated in patients with VS. To screen for RTK activation, surgical VS specimens from patients with and without NF2 were analyzed by phospho-RTK profiling arrays. Downstream signaling pathway activation was analyzed by phospho-MAPK arrays. Activated RTKs and downstream kinases were validated immunohistochemically in corresponding formalin-fixed, paraffin-embedded tissues. Phospho-RTK arrays and immunohistochemistry showed consistent overexpression and activation of EGFR family receptors and evidence of ERK1/2 downstream signaling was observed in all samples analyzed (n = 11). Based on the findings, the small-molecule EGFR/ErbB2 kinase inhibitor lapatinib was selected for evaluation of target inhibition and treatment efficacy in our in vitro human schwannoma model. EGFR/ErbB2 targeted therapy with lapatinib inhibited ErbB2 phosphorylation and survivin upregulation, as well as downstream ERK1/2 and AKT activation, resulting in decreased proliferation. We conclude that EGFR family receptor activation is a consistent feature of both sporadic and NF2-related VS. Molecular targeted therapy with lapatinib downregulates survivin and has antiproliferative activity in a preclinical VS model. Based on these findings, a clinical trial with lapatinib for the treatment of VS is currently underway. © The Author(s) 2010.
Sneyd J.R.,University of Plymouth |
Sneyd J.R.,Research Way |
Holmes K.A.,Plymouth Hospitals NHS Trust
Current Opinion in Anaesthesiology | Year: 2011
Purpose of Review: The comparison of inhalational and intravenous anaesthesia has been the subject of many controlled trials and meta-analyses. These reported diverse endpoints typically including measures of the speed and quality of induction of anaesthesia, haemodynamic changes, operating conditions, various measures of awakening, postoperative nausea and vomiting and discharge from the recovery area and from hospital as well as recovery of psychomotor function. In a more patient-focused Health Service, measures with greater credibility are overall patient satisfaction, time to return to work and long-term morbidity and mortality. In practice, studies using easier to measure proxy endpoints dominate - even though the limitations of such research are well known. Recent Findings: Recent study endpoints are more ambitious and include impact on survival from cancer and the possibility of differential neurotoxic impact on the developing brain and implications for neuro-behavioural performance. Summary: Economic analysis of anaesthesia is complex and most published studies are naive, focusing on drug acquisition costs and facility timings, real health economics are much more difficult. Preferred outcome measures would be whole institution costs or the ability to reliably add an extra case to an operating list, close an operating room and reduce the number of operating sessions offered or permanently decrease staffing. Alongside this, however, potential long-term patient outcomes should be considered. © 2011 Wolters Kluwer Health | Lippincott Williams & Wilkins.
Dogra Y.,University of Exeter |
Ferguson D.C.J.,University of Exeter |
Dodd N.J.F.,University of Plymouth |
Smerdon G.R.,Research Way |
And 2 more authors.
Redox Biology | Year: 2016
Methyl-aminolevulinate-based photodynamic therapy (MAL-PDT) is utilised clinically for the treatment of non-melanoma skin cancers and pre-cancers and the hydroxypyridinone iron chelator, CP94, has successfully been demonstrated to increase MAL-PDT efficacy in an initial clinical pilot study. However, the biochemical and photochemical processes leading to CP94-enhanced photodynamic cell death, beyond the well-documented increases in accumulation of the photosensitiser protoporphyrin IX (PpIX), have not yet been fully elucidated. This investigation demonstrated that MAL-based photodynamic cell killing of cultured human squamous carcinoma cells (A431) occurred in a predominantly necrotic manner following the generation of singlet oxygen and ROS. Augmenting MAL-based photodynamic cell killing with CP94 co-treatment resulted in increased PpIX accumulation, MitoSOX-detectable ROS generation (probably of mitochondrial origin) and necrotic cell death, but did not affect singlet oxygen generation. We also report (to our knowledge, for the first time) the detection of intracellular PpIX-generated singlet oxygen in whole cells via electron paramagnetic resonance spectroscopy in conjunction with a spin trap. © 2016 The Authors.
PubMed | Research Way
Type: Journal Article | Journal: Neuro-oncology | Year: 2011
Loss of the tumor suppressor merlin is a cause of frequent tumors of the nervous system, such as schwannomas, meningiomas, and ependymomas, which occur spontaneously or as part of neurofibromatosis type 2 (NF2). Because there is medical need for drug therapies for these tumors, our aim is to find therapeutic targets. We have studied the pathobiology of schwannomas, because they are the most common merlin-deficient tumors and are a model for all merlin-deficient tumors. With use of a human schwannoma in vitro model, we previously described strong overexpression/activation of platelet-derived growth factor receptor- (PDGFR-) leading to strong, long-lasting activation of extracellular-signal-regulated kinase (ERK1/2) and AKT and increased schwannoma growth, which we successfully inhibited using the PDGFR/Raf inhibitor sorafenib. However, the benign character of schwannomas may require long-term treatment; thus, drug tolerability is an issue. With the use of Western blotting, proliferation assays, viability assays, and a primary human schwannoma cell in vitro model, we tested the PDGFR/c-KIT inhibitors imatinib (Glivec(;) Novartis) and nilotinib (Tasigna(;) Novartis). Imatinib and nilotinib inhibited PDGF-DD-mediated ERK1/2 activation, basal and PDGF-DD-mediated activation of PDGFR- and AKT, and schwannoma proliferation. Nilotinib is more potent than imatinib, exerting its maximal inhibitory effect at concentrations lower than steady-state trough plasma levels. In addition, nilotinib combined with the MEK1/2 inhibitor selumetinib (AZD6244) at low concentrations displayed stronger efficiency toward tumor growth inhibition, compared with nilotinib alone. We suggest that therapy with nilotinib or combinational therapy that simultaneously inhibits PDGFR and the downstream Raf/MEK1/2/ERK1/2 pathway could represent an effective treatment for schwannomas and other merlin-deficient tumors.