Cytokine Levels Correlate with Immune Cell Infiltration after Anti-VEGF Therapy in Preclinical Mouse Models of Breast Cancer

The effect of blocking VEGF activity in solid tumors extends beyond inhibition of angiogenesis. However, no studies have compared the effectiveness of mechanistically different anti-VEGF inhibitors with respect to changes in tumor growth and alterations in the tumor microenvironment. In this study we use three distinct breast cancer models, a MDA-MB-231 xenograft model, a 4T1 syngenic model, and a transgenic model using MMTV-PyMT mice, to explore the effects of various anti-VEGF therapies on tumor vasculature, immune cell infiltration, and cytokine levels. Tumor vasculature and immune cell infiltration were evaluated using immunohistochemistry. Cytokine levels were evaluated using ELISA and electrochemiluminescence. We found that blocking the activation of VEGF receptor resulted in changes in intra-tumoral cytokine levels, specifically IL-1β, IL-6 and CXCL1. Modulation of the level these cytokines is important for controlling immune cell infiltration and ultimately tumor growth. Furthermore, we demonstrate that selective inhibition of VEGF binding to VEGFR2 with r84 is more effective at controlling tumor growth and inhibiting the infiltration of suppressive immune cells (MDSC, Treg, macrophages) while increasing the mature dendritic cell fraction than other anti-VEGF strategies. In addition, we found that changes in serum IL-1β and IL-6 levels correlated with response to therapy, identifying two possible biomarkers for assessing the effectiveness of anti-VEGF therapy in breast cancer patients

Metabolic Versatility and Antibacterial Metabolite Biosynthesis Are Distinguishing Genomic Features of the Fire Blight Antagonist Pantoea vagans C9-1

Smits THM, Rezzonico F, Kamber T, et al. Metabolic Versatility and Antibacterial Metabolite Biosynthesis Are Distinguishing Genomic Features of the Fire Blight Antagonist Pantoea vagans C9-1. PLoS ONE. 2011;6(7): e22247.Background: Pantoea vagans is a commercialized biological control agent used against the pome fruit bacterial disease fire blight, caused by Erwinia amylovora. Compared to other biocontrol agents, relatively little is currently known regarding Pantoea genetics. Better understanding of antagonist mechanisms of action and ecological fitness is critical to improving efficacy. Principal Findings: Genome analysis indicated two major factors contribute to biocontrol activity: competition for limiting substrates and antibacterial metabolite production. Pathways for utilization of a broad diversity of sugars and acquisition of iron were identified. Metabolism of sorbitol by P. vagans C9-1 may be a major metabolic feature in biocontrol of fire blight. Biosynthetic genes for the antibacterial peptide pantocin A were found on a chromosomal 28-kb genomic island, and for dapdiamide E on the plasmid pPag2. There was no evidence of potential virulence factors that could enable an animal or phytopathogenic lifestyle and no indication of any genetic-based biosafety risk in the antagonist. Conclusions: Identifying key determinants contributing to disease suppression allows the development of procedures to follow their expression in planta and the genome sequence contributes to rationale risk assessment regarding the use of the biocontrol strain in agricultural systems

Tumour macrophages as potential targets of bisphosphonates

Tumour cells communicate with the cells of their microenvironment via a series of molecular and cellular interactions to aid their progression to a malignant state and ultimately their metastatic spread. Of the cells in the microenvironment with a key role in cancer development, tumour associated macrophages (TAMs) are among the most notable. Tumour cells release a range of chemokines, cytokines and growth factors to attract macrophages, and these in turn release numerous factors (e.g. VEGF, MMP-9 and EGF) that are implicated in invasion-promoting processes such as tumour cell growth, flicking of the angiogenic switch and immunosuppression. TAM density has been shown to correlate with poor prognosis in breast cancer, suggesting that these cells may represent a potential therapeutic target. However, there are currently no agents that specifically target TAM's available for clinical use

Bias of health estimates obtained from chronic disease and risk factor surveillance systems using telephone population surveys in Australia: Results from a representative face-to-face survey in Australia from 2010 to 2013

Background: Emerging communication technologies have had an impact on population-based telephone surveys worldwide. Our objective was to examine the potential biases of health estimates in South Australia, a state of Australia, obtained via current landline telephone survey methodologies and to report on the impact of mobile-only household on household surveys. Methods: Data from an annual multi-stage, systematic, clustered area, face-to-face population survey, Health Omnibus Survey (approximately 3000 interviews annually), included questions about telephone ownership to assess the population that were non-contactable by current telephone sampling methods (2006 to 2013). Univariable analyses (2010 to 2013) and trend analyses were conducted for sociodemographic and health indicator variables in relation to telephone status. Relative coverage biases (RCB) of two hypothetical telephone samples was undertaken by examining the prevalence estimates of health status and health risk behaviours (2010 to 2013): directory-listed numbers, consisting mainly of landline telephone numbers and a small proportion of mobile telephone numbers; and a random digit dialling (RDD) sample of landline telephone numbers which excludes mobile-only households. Results: Telephone (landline and mobile) coverage in South Australia is very high (97 %). Mobile telephone ownership increased slightly (7.4 %), rising from 89.7 % in 2006 to 96.3 % in 2013; mobile-only households increased by 431 % over the eight year period from 5.2 % in 2006 to 27.6 % in 2013. Only half of the households have either a mobile or landline number listed in the telephone directory. There were small differences in the prevalence estimates for current asthma, arthritis, diabetes and obesity between the hypothetical telephone samples and the overall sample. However, prevalence estimate for diabetes was slightly underestimated (RCB value of -0.077) in 2013. Mixed RCB results were found for having a mental health condition for both telephone samples. Current smoking prevalence was lower for both hypothetical telephone samples in absolute differences and RCB values: -0.136 to -0.191 for RDD landline samples and -0.129 to -0.313 for directory-listed samples. Conclusion: These findings suggest landline-based sampling frames used in Australia, when appropriately weighted, produce reliable representative estimates for some health indicators but not for all. Researchers need to be aware of their limitations and potential biased estimates.Emerging communication technologies have had an impact on population-based telephone surveys worldwide. Our objective was to examine the potential biases of health estimates in South Australia, a state of Australia, obtained via current landline telephone survey methodologies and to report on the impact of mobile-only household on household surveys

Expression of two WFDC1/ps20 isoforms in prostate stromal cells induces paracrine apoptosis through regulation of PTGS2/COX-2

Background: WFDC1/Prostate stromal 20 (ps20) is a small secreted protein highly expressed within the prostate stroma. WFDC1/ps20 expression is frequently downregulated or lost in prostate cancer (PCa) and ps20 has demonstrated growth-suppressive functions in numerous tumour model systems, although the mechanisms of this phenomenon are not understood. Methods: Ps20 was cloned and overexpressed in DU145, PC3, LNCaP and WPMY-1 cells. Cellular growth, cell cycle and apoptosis were characterised. WPMY-1 stromal cells expressing ps20 were characterised by transcriptome microarray and the function of WPMY-1 conditioned media on growth of PCa cell lines was assessed. Results: Prostrate stromal 20 expression enhanced the proliferation of LNCaP cells, whereas stromal WPMY-1 cells were inhibited and underwent increased apoptosis. Prostrate stromal 20-expressing WPMY-1 cells secrete a potently proapoptotic conditioned media. Prostrate stromal 20 overexpression upregulates expression of cyclooxygenase-2 (COX-2) in LNCaP and WPMY-1 cells, and induces expression of a growth-suppressive phenotype, which inhibits proliferation of PCa cells by ps20-expressing WPMY-1 conditioned media. This growth suppression was subsequently shown to be dependent on COX-2 function. Conclusions: This work posits that expression of ps20 in the prostate stroma can regulate growth of epithelial and other tissues through the prostaglandin synthase pathway, and thereby restricts development and progression of neoplasms. This provides a rational for selective pressure against ps20 expression in tumour-associated stroma