New vaccine formulations that include novel strains of Mycoplasma hyopneumoniae and innovative adjuvants designed to induce cellular immunity could improve vaccine efficacy against this pathogen. The aim of this experimental study was to assess the efficacy of three experimental bacterin formulations based on M. hyopneumoniae field strain F7.2C which were able to induce cellular immunity. The formulations included a cationic liposome formulation with the Mincle receptor ligand trehalose 6,6-dibehenate (Lipo_DDA:TDB), a squalene-in-water emulsion with Toll-like receptor (TLR) ligands targeting TLR1/2, TLR7/8 and TLR9 (SWE_TLR), and a poly(lactic-co-glycolic acid) micro-particle formulation with the same TLR ligands (PLGA_TLR). Four groups of 12 M. hyopneumoniae-free piglets were primo- (day (D) 0; 39 days of age) and booster vaccinated (D14) intramuscularly with either one of the three experimental bacterin formulations or PBS. The pigs were endotracheally inoculated with a highly and low virulent M. hyopneumoniae strain on D28 and D29, respectively, and euthanized on D56. The main efficacy parameters were: respiratory disease score (RDS; daily), macroscopic lung lesion score (D56) and log copies M. hyopneumoniae DNA determined with qPCR on bronchoalveolar lavage (BAL) fluid (D42, D56). All formulations were able to reduce clinical symptoms, lung lesions and the M. hyopneumoniae DNA load in the lung, with formulation SWE_TLR being the most effective (RDSD28–D56 −61.90%, macroscopic lung lesions −88.38%, M. hyopneumoniae DNA load in BAL fluid (D42) −67.28%). Further experiments raised under field conditions are needed to confirm these results and to assess the effect of the vaccines on performance parameters.

Predictive preventive personalized medicine Liver cancer is the fifth most common form of cancer worldwide [1], with an incidence rate almost equals the mortality rate and ranks 3 rd among causes of cancer related death [2]. The coexistence of two life threatening conditions, cancer and liver cirrhosis makes the staging challenging. However, there are some staging systems, e.g. the Barcelona staging system for Hepatocellular carcinoma (HCC) [3], that suggest treatment options and management. Whereas diagnosis in early stages gives hope for a curative outcome, the treatment regime for around 80 % [2] of the patients classified as severe stages only gears towards palliation [4]. An intra-arterial radiation approach, radioembolisation (RE) is ubiquitously applied as one of palliative approaches. Although, in general RE shows promising results in intermediate and advanced stage HCC [5], individual treatment outcomes are currently unpredictable. Corresponding stratification criteria are still unclear. We hypothesised that individual radioresistance/radiosensitivity may play a crucial role in treatment response towards RE strongly influencing individual outcomes. Further, HCC represents a highly heterogeneous group of patients which requires patient stratification according to clear criteria for treatment algorithms to be applied individually. Multilevel diagnostic approach (MLDA) is considered helpful to set-up optimal predictive and prognostic biomarker panel for individualised application of radioembolisation. Besides comprehensive medical imaging, our MLDA includes non-invasive multi-omics and sub-cellular imaging. Individual patient profiles are expected to give a clue to targeting shifted molecular pathways, individual RE susceptibility, treatment response. Hence, a dysregulation of the detoxification pathway (SOD2/Catalase) might indicate possible adverse effects of RE, and highly increased systemic activities of matrix metalloproteinases indicate an enhanced tumour aggressiveness and provide insights into molecular mechanisms/targets. Consequently, an optimal set-up of predictive and prognostic biomarker panels may lead to the changed treatment paradigm from untargeted "treat and wait" to the cost-effective predictive, preventive and personalised approach, improving the life quality and life expectancy of HCC patients. Keywords: Market access, Value, Strategy, Companion diagnostics, Cost-effectiveness, Reimbursement, Health technology assessment, Economic models, Predictive preventive personalized medicine Achieving and sustaining seamless "drug -companion diagnostic" market access requires a sound strategy throughout a product life cycle, which enables timely creation, substantiation and communication of value to key stakeholders [1, 2]. The study aims at understanding the root-cause of market access inefficiencies of companies by gazing at the "Rx-CDx" co-development process through the prism of "value", and developing a perfect co-development scenario based on the literature review and discussions with the ...

Background Porcine ear necrosis (PEN) in pigs is characterized by a blue to black discoloration of the tip or margin of the ear followed by necrosis. The present study investigated the prevalence of PEN in a Belgian pig farm with PEN problems in nursery pigs, the effect of a mycotoxin detoxifier added to the feed on PEN prevalence, and the impact of PEN on the piglets’ growth. Six consecutive batches of weaned piglets [565–751 piglets per batch, (n = 3898)] were included. For each weaning batch, the presence and severity of PEN during the nursery period (3–10 weeks of age) were recorded weekly. Average daily gain (ADG) was calculated by weighing 597 individual piglets divided over the six batches. Additionally different mycotoxins were measured in the feed using LC–MS/MS analysis, and to three randomly selected batches, a mycotoxin detoxifier (Mycofix® Plus 5E, Biomin) was added to the feed. Results At the end of the nursery period, 11.0–32.0% of the piglets in each batch were affected. The prevalence increased with the number of weeks post-weaning, especially from week 4 after weaning onwards. Mild, moderate, severe and very severe lesions represented 84.6%, 14.0%, 1.3% and 0.1% of all lesions, respectively. Different mycotoxins were present in the feed, but all at low concentrations. The mean ADG (± SD) for pigs without (n = 243) and with (n = 158) lesions was 391 g (± 71 g) and 394 g (± 65 g), respectively (P > 0.05). The ADG for mildly affected (387 g ± 68 g) and moderately affected piglets (420 g ± 44 g) was not significantly different (P > 0.05). The PEN prevalence in the batches without or with the mycotoxin detoxifier was 25% and 22%, respectively (P > 0.05). Conclusions Twenty-three percent of animals showed lesions at the end of the nursery. Affected pigs did not have a lower ADG compared to non-affected animals, which might be explained by the fact that most affected piglets only had mild lesions. The addition of a mycotoxin detoxifier did not influence the prevalence of PEN, possibly because of the low levels of mycotoxin contamination. Further research is warranted to assess the impact of more severe PEN lesions and the effect of control measures.

ObjectiveTreatment of inflammation and pain management is an important topic in the welfare of pigs. It is very difficult for veterinary practitioners to choose the most appropriate product for a certain problem. This review aims to summarise and discuss the characteristics of different non-steroidal anti-inflammatory drugs (NSAIDs), as well as paracetamol and metamizole, available for pigs in the European Union.MethodsThe databases Pubmed, Google Scholar, CliniPharm CliniTox and European Medicines Agency were searched. Relevant terms (eg,‘meloxicam’, ‘fever’, ‘swine’, ‘pig’, ‘inflammation’, ‘castration’, ‘pain’) were used to search for original articles, reviews and books. Only peer-reviewed articles were used. References from studies were also analysed in order to find additional relevant studies.ConclusionStudies which have investigated the efficacy of NSAIDs for different conditions, using different treatment regimens, are scarce. Most studies focused on the efficacy of NSAID-related pain alleviation in piglet castration, as well as the anti-inflammatory potential of NSAIDs in experimental inflammation models. Little research has been carried out on the use of metamizole, tolfenamic acid, paracetamol and sodium salicylate and their effect in pigs.

Opioids promote tumor angiogenesis in mammary malignancies, but the underlying signaling mechanism is largely unknown. The current study investigated the hypothesis that stimulation of d-opioid receptors (DOR) in breast cancer (BCa) cells activates the hypoxia-inducible factor 1a (HIF-1a), which triggers synthesis and release of diverse angiogenic factors. Immunoblotting revealed that incubation of human MCF-7 and T47D breast cancer cells with the DOR agonist D-Ala 2 ,D-Leu 5-enkephalin (DADLE) resulted in a transient accumulation and thus activation of HIF-1a. DADLE-induced HIF-1a activation preceded PI3K/Akt stimulation and was blocked by the DOR antagonist naltrindole and naloxone, pertussis toxin, different phosphoinositide 3-kinase (PI3K) inhibitors, and the Akt inhibitor Akti-1/2. Whereas DADLE exposure had no effect on the expression and secretion of vascular endothelial growth factor (VEGF) in BCa cells, an increased abundance of cyclooxygenase-2 (COX-2) and release of prostaglandin E2 (PGE 2) was detected. DADLE-induced COX-2 expression was also observed in three-dimensional cultured MCF-7 cells and impaired by PI3K/Akt inhibitors and the HIF-1a inhibitor echinomycin. Supernatant from DADLEtreated MCF-7 cells triggered sprouting of endothelial (END) cells, which was blocked when MCF-7 cells were pretreated with echinomycin or the COX-2 inhibitor celecoxib. Also no sprouting was observed when END cells were exposed to the PGE 2 receptor antagonist PF-04418948. The findings together indicate that DOR stimulation in BCa cells leads to PI3K/Aktdependent HIF-1a activation and COX-2 expression, which trigger END cell sprouting by paracrine activation of PGE 2 receptors. These findings provide a potential mechanism of opioid-driven tumor angiogenesis and thus therapeutic targets to combat the tumor-angiogenic opioid effect. SIGNIFICANCE STATEMENT Opioids are indispensable analgesics for treating cancer-related pain. However, opioids were found to promote tumor growth and metastasis, which questions the use of these potent painrelieving drugs in cancer patients. Enhanced tumor vascularization after opioid treatment implies that tumor progression results from angiogenic opioid effects. Thus, understanding the signaling mechanism of opioid-driven tumor angiogenesis helps to identify therapeutic targets to combat these undesired tumor effects. The present study reveals that stimulation of d-opioid receptors in breast cancer cells leads to an activation of HIF-1a and expression of COX-2 via PI3K/Akt stimulation, which results in a paracrine activation of vascular endothelial cells by prostaglandin E 2 receptors.