Aims: The aim of this study was to examine the antimicrobial properties of novel aqueous natural rapeseed oil/saline emulsions containing different soluble components of spruce resin. Methods and Results: The composition of aqueous resin emulsions was analysed by GC-MS and their antimicrobial properties were studied with challenge tests and with turbidometric assays. The emulsions were strongly antimicrobial against common Gram-positive and Gram-negative bacteria (including MRSA) as well as common yeasts. Furthermore, they inhibited the biofilm formation and eradicated the microbial biofilms on tested microbes. Characteristic for the emulsions was the presence of oxidized resin acids. Other main components present in emulsions, such as lignans and coumaric acids, were not antimicrobial, when tested separately. Conclusions:The results indicated that the oxidized resin acids were the antimicrobial components in the emulsions. Also, there appears to be a stoichiometric relationship between the number of resin acid molecules and the number microbe cells in the antimicrobial action. Significance and Impact of the Study: The fact that these solutions do not contain abietic acid, which is the main allergenic compound in resins, suggests that these solutions would be suitable, well-tolerated antimicrobials for various medical applications. The aqueous formulation will also allow the expansion of the use of these emulsions in from medical applications to the food preservatives and disinfectants. IntroductionCreams or salves based on natural resins collected from trunks ("callus" resin) of Norway spruce (Picea abies), have been used as home-made remedies for skin wounds and infections for hundreds of years (Cowan 1999;Kalemba and Kunicka 2003;Mahady 2005;Rautio et al. 2007;Sipponen 2013). The water-insoluble main resin acids (e.g. abietic acids or dehydroabietic acid) in coniferous resins have been shown to be antimicrobial and antifungal in several previous studies (S€ oderberg et al. 1990;Savluchinske Feio et al. 1999;Rautio et al. 2007Rautio et al. , 2012Sipponen and Laitinen 2011). However, the poor solubility in water limits their applicability as microbicidal agents, or as modern liquid antiseptics (Peng and Roberts 2000;Keeling and Bohlmann 2006).A novel method to disperse the partially soluble components of natural coniferous resins into water makes the manufacturing of aqueous resin emulsions possible. However, this might lead to the loss antimicrobial properties due to the exclusion of resin acids. In this study, we examined the retained antimicrobial activities of two 136

Background and Aims Natural coniferous resins are used in traditional medicine for the treatment of skin wounds. Coniferous wood resins (“callus” resin) are a mixture of abietic (resin) acids, lignans such as pinoresinol, and p ‐coumaric acid. The wound‐healing properties of resins are thought to be related to their antimicrobial properties, but also to their effects on cell proliferation and inflammation. The purpose of this study was to identify and investigate the effects of novel aqueous dispersions of resin and its main components in the proliferation of human primary keratinocytes in vitro and in the expression of proinflammatory cytokines in human peripheral blood mononuclear cells. Methods The proliferation studies were performed under low and high calcium conditions with or without added growth stimulators at the time points of 2 and 6 days using AlamarBlue Cell Viability Reagent. The cytokine release assay was carried out by incubating the cells with the test articles for 18 h, after which the levels of tumor necrosis factor‐α (TNF‐α), interleukin‐1β (IL‐1β), IL‐6, and IL‐8 were measured in the supernatant by enzyme‐linked immunosorbent assay. Results Resin and the purified lignan PINO, but not p ‐coumaric acid or abietic acid (industrial tall oil rosin), enhanced the proliferation of human keratinocytes in vitro and inhibited the expression of TNF‐α, and to a lesser extent the expression of IL‐1β in peripheral blood mononuclear cells. Conclusions In this study, novel aqueous dispersions of spruce resin were used to investigate the effects of main resin components on keratinocyte proliferation and on the expression of key proinflammatory cytokines known to be associated with chronic wounds. The observations suggest that lignans, such as PINO, but not resin acids, are the components of resins that mediate the proliferative and TNF‐α‐suppressing effects. Lignans including PINO were identified as novel potential compounds in the treatment of chronic skin ulcers.

Traditional preclinical discovery methods and models only poorly predict drug efficacy in clinical trials. It has been reasoned that present cultured tumor cell line and xenotransplantation-based in vivo models are too reductionist, failing to recapitulate tumour heterogeneity, tumor-microenvironment interactions and tumor microevolutionary trajectories. The genetically engineered mouse models (GEMMs) hold promise as next generation preclinical models, but the caveat is that GEMMs are not straightforward suitable for preclinical cohort studies. Here we hypothesized that mammary tumors from tumor-prone WAP-Myc mice retain their molecular characteristics and authentic drug responses when recreated as syngrafts in the mammary fat pads of recipient mouse. This platform would allow rapid and non-laborious pilot cohort studies with GEMM tumors. We are testing the hypothesis by determining tumor markers and apoptotic efficacy of BH3-mimetic ABT-737 against c-Myc-induced mammary adenocarcinomas and pulmonary metastases in both transgenic and syngraft models. In the WAP-Myc mice c-Myc is induced in the luminal mammary epithelial cells during late pregnancy resulting in development of endogeneous mammary adenocarcinomas in nearly 100% of multiparous animals. We observe that the tumors are transplantable as cells suspensions (25 000 cells/gland) with approximately 90% success rate. While the transgenic WAP-Myc tumors develop with an average of 3.5 months latency, the syngrafted tumors develop within 3-4 weeks post-transplantation. However, in contrast to 20% rate of pulmonary metastases in the transgenic WAP-Myc mice, syngrafted animals need to be sacrificed prior to metastasis formation. Our preliminary results suggest that the tumor histopathology does not significantly change and the tumor heterogeneity is preserved in the syngrafted tumors. To investigate the response of tumors to ABT-737, animals bearing either endogenous or transplanted tumors were treated with 100mg/kg of ABT-737 for 21 days. ABT-737 reduced primary tumor growth and lung metastases as well as enhanced caspase-3 activity in the transgenic WAP-Myc tumors. Also the syngrafted tumors respond to ABT-737 and the data comparing effects in transgenic versus syngrafted tumors will be presented. Our results demonstrating feasibility of the syngraft platform may help to alleviate many shortcomings of GEMMs in preclinical studies. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 2389. doi:10.1158/1538-7445.AM2011-2389

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