Association of Canine Osteosarcoma and Monocyte Phenotype and Chemotactic Function

BACKGROUND: Monocytes/macrophages are likely key cells in immune modulation in dogs with osteosarcoma (OSA). Increased peripheral monocyte counts are negatively correlated with shorter disease-free intervals in dogs with OSA. Understanding the monocyte/macrophage's modulatory role in dogs with OSA can direct further studies in immunotherapy development for OSA. HYPOTHESIS/OBJECTIVES: That OSA evades the immune response by down-regulating monocyte chemokine receptor expression and migratory function, and suppresses host immune responses. ANIMALS: Eighteen dogs with OSA that have not received definitive treatment and 14 healthy age-matched controls METHODS: Clinical study-expression of peripheral blood monocyte cell surface receptors, monocyte mRNA expression and cytokine secretion, monocyte chemotaxis, and survival were compared between clinical dogs with OSA and healthy control dogs. RESULTS: Cell surface expression of multiple chemokine receptors is significantly down-regulated in peripheral blood monocytes of dogs with OSA. The percentage expression of CCR2 (median 58%, range 2-94%) and CXCR2 expression (median 54%, range 2-92%) was higher in control dogs compared to dogs with OSA (CCR2 median 29%, range 3-45%, P = 0.0006; CXCR2 median 23%, range 0.2-52%, P = 0.0007). Prostaglandin E2 (PGE2 ) (OSA, median 347.36 pg/mL, range 103.4-1268.5; control, 136.23 pg/mL, range 69.93-542.6, P = .04) and tumor necrosis factor-alpha (TNF-α) (P = .02) levels are increased in OSA monocyte culture supernatants compared to controls. Peripheral blood monocytes of dogs with OSA exhibit decreased chemotactic function when compared to control dogs (OSA, median 1.2 directed to random migration, range 0.8-1.25; control, 1.6, range of 0.9-1.8, P = .018). CONCLUSIONS AND CLINICAL IMPORTANCE: Dogs with OSA have decreased monocyte chemokine receptor expression and monocyte chemotaxis, potential mechanisms by which OSA might evade the immune response. Reversal of monocyte dysfunction using immunotherapy could improve survival in dogs with OSA

A Feline-Specific Anti-Nerve Growth Factor Antibody Improves Mobility in Cats with Degenerative Joint Disease-Associated Pain: A Pilot Proof of Concept Study

BACKGROUND: Neutralizing antibodies against nerve growth factor (NGF) are analgesic in rodent models, naturally occurring degenerative joint disease (DJD) pain in dogs, and chronic pain in humans. OBJECTIVES: To evaluate the efficacy of a fully felinized anti-NGF antibody (NV-02) for the treatment of DJD pain and mobility impairment in cats. ANIMALS: Thirty-four client-owned cats with DJD-associated pain and mobility impairment. METHODS: In a placebo-controlled, pilot, masked clinical study, cats were randomized to a single treatment with NV-02 (0.4 mg/kg SC [n = 11] or 0.8 mg/kg SC [n = 12]) or placebo (saline, SC [n = 11]). Activity was measured objectively. Additionally, owners completed clinical metrology instruments (client-specific outcome measures [CSOM] and feline musculoskeletal pain index [FMPI]) on days 0 (screening), 14 (baseline), 35, 56, and 77. A repeated-measures model was used to evaluate the objective activity data. RESULTS: NV-02 significantly increased objectively measured activity overall (P = .017) and at 2 (P = .035), 3 (P = .007), 4 (P = .006), 5 (P = .007), and 6 (P = .017) weeks after treatment. CSOM scores (P = .035) and pain (P = .024) showed a significant effect of treatment 3 weeks after administration. In the treatment group, 83% of the owners correctly identified the treatment administered compared with 45% of owners in the placebo group (P = .013). No treatment-related adverse effects were identified. CONCLUSIONS: These pilot data demonstrate a 6-week duration positive analgesic effect of this fully felinized anti-NGF antibody in cats suffering from DJD-associated pain

In Vitro and In Vivo Characterization of a Fully Felinized Therapeutic Anti-Nerve Growth Factor Monoclonal Antibody for the Treatment of Pain in Cats

BACKGROUND: Limited options are available for the treatment of pain in cats. Monoclonal antibodies (mAbs) that neutralize nerve growth factor (NGF) have demonstrated analgesic capacity in rodent models, people with osteoarthritis, and dogs with degenerative joint disease. HYPOTHESIS/OBJECTIVES: This study describes the design and characterization of a fully felinized anti-NGF monoclonal antibody. In vitro potency, pharmacokinetics, and the ability of the antibody to treat pain in a self-resolving, acute inflammation model were investigated in cats. ANIMALS: Thirty-eight cats at a research colony at Charles River Laboratories, Ireland. METHODS: Felinized anti-NGF mAb, NV-02, was produced using a complementary DNA (cDNA)-based method (PETization). Purified NV-02 was tested for affinity, potency, and immunoreactivity in vitro, then for safety and plasma pharmacokinetic distribution in vivo, and analgesic efficacy in a model of kaolin-induced inflammatory pain. RESULTS: Anti-NGF mAb, NV-02 neutralized NGF with high affinity and potency and did not bind complement. NV-02-administered SC had a plasma half-life of 7-15 days and was well tolerated at dosages up to 28 mg/kg. A dosage of 2 mg/kg NV-02 SC significantly decreased signs of lameness on day 2 (P = .0027), day 3 (P = .016), day 4, (P = .0063), day 5 (P = .0085), day 6 (P = .0014), and day 7 (P = .0034) after induction of inflammation. CONCLUSIONS AND CLINICAL IMPORTANCE: The high affinity, long plasma half-life, safety, and analgesic efficacy of felinized anti-NGF mAb (NV-02) support further investigation of the analgesic potential of this antibody in the cat

Systematic review of the behavioural assessment of pain in cats

Objectives The objectives were to review systematically the range of assessment tools used in cats to detect the behavioural expression of pain and the evidence of their quality; and to examine behavioural metrics (considering both the sensory and affective domains) used to assess pain. Methods A search of PubMed and ScienceDirect, alongside articles known to the authors, from 2000 onwards, for papers in English was performed. This was followed by a manual search of the references within the primary data sources. Only peer-reviewed publications that provided information on the assessment tool used to evaluate the behavioural expression of pain in cats, in conscious animals (not anaesthetised cats), were included. Results No previous systematic reviews were identified. One hundred papers were included in the final assessment. Studies were primarily related to the assessment of pain in relation to surgical procedures, and no clear distinction was made concerning the onset of acute and chronic pain. Ten broad types of instrument to assess pain were identified, and generally the quality of evidence to support the use of the various instruments was poor. Only one specific instrument (UNESP-Botucatu scale) had published evidence of validity, reliability and sensitivity at the level of a randomised control trial, but with a positive rather than placebo control, and limited to its use in the ovariohysterectomy situation. The metrics used within the tools appeared to focus primarily on the sensory aspect of pain, with no study clearly discriminating between the sensory and affective components of pain. Conclusions and relevance Further studies are required to provide a higher quality of evidence for methods used to assess pain in cats. Furthermore, a consistent definition for acute and chronic pain is needed. Tools need to be validated that can detect pain in a range of conditions and by different evaluators (veterinary surgeons and owners), which consider both the sensory and emotional aspects of pain

Key Sustainable Supply Chain Management Processes - A conceptual framework grounded in network theory.

The purpose of this paper is to outline a conceptual framework of the key processes that integrate sustainability across the supply chain strategically. This has not been done to date due to several factors including the nascent nature of sustainable supply chain management (SCM) research; increased complexities in SCM such as a proliferation of perspectives given various foci of disciplines, theoretical lenses and stakeholder perspectives; and ever more complex strategies given the added sustainable components. With the maturation of this field, the business case as to why sustainability criteria should be integrated in to core business operations has been well established. Piloted sustainable supply chains are coming of age and are exemplified as flagship business practices in company sustainability reports. Practitioners and academics are now turning to the problem of scaling up processes, not only across the whole supply chain, but across the network too. There is no research that systematically maps processes that integrate sustainability dimensions across the supply chain. This presented an opportunity to develop a conceptual framework, outlining the content from themes and issues in SCM and sustainability processes. Through the literature reviewed, key issues in sustainable SCM and its key processes were identified. Furthermore, key findings indicate that there are divergent interests in sustainability agendas across all disciplines and stakeholders that affect how these processes are integrated. This suggests how sustainability is perceived and integrated, requires further attention. To help frame the understanding of how these processes are managed, given the factors at play, the framework is built upon the theoretical proposition of Network Theory (NT), and the influence of power and decision-making. The aim is to develop a theoretical understanding of sustainable SCM with the intention of making an original contribution to the supply chain discipline

Critical evaluation of epistemology in supply chain research - Qualitative case study research in operations and supply chain management.

The purpose of this paper is to offer a critical evaluation of epistemology in supply chain research. The two approaches, the positivist and post-positivist critical realism research traditions, are the primary philosophical foundations for case study research design. These are discussed in relation to the research project: ‘exploring sustainable supply chain strategy’. Key concepts in the literature present characteristics of the research problem in relation to the methodological paradigm and theory development from which a summary that underpins the research strategy is outlined in the ‘Research method’ section. Finally, the research questions leading from the findings are presented

Key sustainable supply chain processes: a conceptual framework

The purpose of this paper is to outline a conceptual framework of the key processes that integrate sustainability across the supply chain strategically. This has not been done to date due to several factors including the nascent nature of sustainable supply chain management (SCM) research; increased complexities in SCM such as a proliferation of perspectives given various foci of disciplines, theoretical lenses and stakeholder perspectives; and ever more complex strategies given the added sustainable components. With the maturation of this field, the business case as to why sustainability criteria should be integrated in to core business operations has been well established. Piloted sustainable supply chains are coming of age and are exemplified as flagship business practices in company sustainability reports. Practitioners and academics are now turning to the problem of scaling up processes, not only across the whole supply chain, but across the network too. There is no research that systematically maps processes that integrate sustainability dimensions across the supply chain. This presented an opportunity to develop a conceptual framework, outlining the content from themes and issues in SCM and sustainability processes. Through the literature reviewed, key issues in sustainable SCM and its key processes were identified. Furthermore, key findings indicate that there are divergent interests in sustainability agendas across all disciplines and stakeholders that affect how these processes are integrated. This suggests how sustainability is perceived and integrated, requires further attention. To help frame the understanding of how these processes are managed, given the factors at play, the framework is built upon the theoretical proposition of Network Theory (NT), and the influence of power and decision-making. The aim is to develop a theoretical understanding of sustainable SCM with the intention of making an original contribution to the supply chain discipline

Eight Challenges of Servitization for the Configuration, Measurement and Management of Organisations

Purpose – There is an extensive research literature on servitisation and the related field of product-service systems that has emerged independently from different fields including engineering, management, design and environmental studies. The purpose of this paper is to conduct a structured literature review to explore, identify and synthesise the multi-disciplinary research challenges in the journey towards servitisation. Design/methodology/approach – The research approach is a systematic literature review using key word searches and citation tracking for research reported between 1990 and 2013 in research databases that cover the fields which have generated the body of knowledge. Findings – One of the key findings from the extant literature on servitisation is that it suffers from three fundamental weaknesses. First, numerous studies are conceptual in nature with limited practicality. Second, there are relatively few empirical studies, and often the findings relate to a single case study based on the insights of a limited number of senior managers. Third, often the dynamics are insufficiently studied in these organisations because data for most cases are collected post-event. Research limitations/implications – Based on the literature review and its shortfalls, this paper proposes a holistic framework of eight themes that require further attention from academic researchers in order that a more complete conceptual understanding of servitisation is developed to support practice. Practical implications – Each theme in the framework has an associated list of questions that can be addressed through research and presented to managers as a challenge agenda to improve their servitisation efforts. That servitisation is associated with differentiation and competitive advantage makes this a valuable approach for managing corporate performance. Originality/value – Research from multi-disciplinary sources is synergised in order to develop an overarching servitisation agenda that transcends domain-based boundaries. This paves the way for an approach to servitisation that is coherent and harmonious

Pilot evaluation of a novel unilateral onychectomy model and efficacy of an extended release buprenorphine product

Abstract Background Non-steroidal anti-inflammatory drugs (NSAIDs), transdermal fentanyl patches, and transmucosal buprenorphine are probably the most commonly used options for providing post-operative analgesia in the early at-home period. However, these require daily administration or are associated with abuse concerns. One of the significant unmet needs in veterinary surgery and pain management is for longer acting opioids for cats to effectively bridge the gap between the in-hospital and at-home recovery periods. A proof of concept study of an extended release formulation of buprenorphine HCL (ER-Bup) was conducted using objective kinetic measures and a unilateral onychectomy model. Using a blinded, randomized, two period crossover design, four cats were allocated to control (saline) or ER-Bup (0.6 mg/kg, subcutaneously [SC]) treatment groups. All animals underwent a unilateral forelimb onychectomy per period with a washout/recovery period in between. Observational pain scores and kinetic data (using a pressure sensitive walkway [PSW]) were collected prior to (baseline) and at intervals for 72 h following surgery. Symmetry indices were derived for kinetic variables (peak vertical force [PVF]; vertical impulse [VI]) of each forelimb for landing following a jump and for walking. A rescue analgesic protocol was in place. Effect of surgery and treatment were evaluated using a mixed model statistical approach. Results No cats required rescue analgesics based on subjective pain score. ER-Bup had a positive influence on subjective pain scores during the 72 h postsurgery (p = 0.0473). PVF and VI of the operated limb were significantly decreased for both landing (p < 0.0001 and p < 0.0001) and walking (p < 0.0001 and p < 0.0001 respectively) compared to control. ER-Bup resulted in significantly decreased asymmetry in limb use during landing (PVF, p < 0.0001; VI, p < 0.0001) and walking (PVF, p = 0.0002, VI, p < 0.0001). The novel use of data collected following a jump from an elevated platform appeared to provide all desired information and was easier to collect than walking data. Conclusion This study demonstrates that SC administration of ER-Bup may be an effective analgesic for a 72 h period postoperatively. Furthermore, landing onto a PSW from an elevated perch may be a useful and efficient way to assess analgesics in cats using a unilateral model of limb pain