Quantitative image analysis of intra-tumoral bFGF level as a molecular marker of paclitaxel resistance

<p>Abstract</p> <p>Background</p> <p>The role of basic fibroblast growth factor (bFGF) in chemoresistance is controversial; some studies showed a relationship between higher bFGF level and chemoresistance while other studies showed the opposite finding. The goal of the present study was to quantify bFGF levels in archived tumor tissues, and to determine its relationship with chemosensitivity.</p> <p>Methods</p> <p>We established an image analysis-based method to quantify and convert the immunostaining intensity of intra-tumor bFGF to concentrations; this was accomplished by generating standard curves using human xenograft tumors as the renewable tissue source for simultaneous image analysis and ELISA. The relationships between bFGF concentrations and tumor chemosensitivity of patient tumors (n = 87) to paclitaxel were evaluated using linear regression analysis.</p> <p>Results</p> <p>The image analysis results were compared to our previous results obtained using a conventional, semi-quantitative visual scoring method. While both analyses indicated an inverse relationship between bFGF level and tumor sensitivity to paclitaxel, the image analysis method, by providing bFGF levels in individual tumors and therefore more data points (87 numerical values as opposed to four groups of staining intensities), further enabled the quantitative analysis of the relationship in subgroups of tumors with different pathobiological properties. The results show significant correlation between bFGF level and tumor sensitivity to the antiproliferation effect, but not the apoptotic effect, of paclitaxel. We further found stronger correlations of bFGF level and paclitaxel sensitivity in four tumor subgroups (high stage, positive p53 staining, negative aFGF staining, containing higher-than-median bFGF level), compared to all other groups. These findings suggest that the relationship between intra-tumoral bFGF level and paclitaxel sensitivity was context-dependent, which may explain the previous contradictory findings on the merit of using plasma or urine bFGF level as a prognostic indicator.</p> <p>Conclusion</p> <p>The present study established a quantitative image analysis method that enabled the measurement of intratumoral bFGF level in archived tissues. The ability to quantify a potential biomarker provided the opportunity to study the relationship between the biomarker and chemosensitivity in tumor subgroups and thereby enabled hypothesis generation for additional translational research.</p

Association of Nonsteroidal Anti-Inflammatory Drugs with Lung Cancer: Results from a Large Cohort Study

Lung cancer is the most common cause of cancer-related mortality. Smoking cessation is crucial to decrease risk but additional prevention modalities are needed. Use of non-steroidal anti-inflammatory drugs (NSAIDs) may be promising

Intravesical Treatments of Bladder Cancer: Review

For bladder cancer, intravesical chemo/immunotherapy is widely used as adjuvant therapies after surgical transurethal resection, while systemic therapy is typically reserved for higher stage, muscle-invading, or metastatic diseases. The goal of intravesical therapy is to eradicate existing or residual tumors through direct cytoablation or immunostimulation. The unique properties of the urinary bladder render it a fertile ground for evaluating additional novel experimental approaches to regional therapy, including iontophoresis/electrophoresis, local hyperthermia, co-administration of permeation enhancers, bioadhesive carriers, magnetic-targeted particles and gene therapy. Furthermore, due to its unique anatomical properties, the drug concentration-time profiles in various layers of bladder tissues during and after intravesical therapy can be described by mathematical models comprised of drug disposition and transport kinetic parameters. The drug delivery data, in turn, can be combined with the effective drug exposure to infer treatment efficacy and thereby assists the selection of optimal regimens. To our knowledge, intravesical therapy of bladder cancer represents the first example where computational pharmacological approach was used to design, and successfully predicted the outcome of, a randomized phase III trial (using mitomycin C). This review summarizes the pharmacological principles and the current status of intravesical therapy, and the application of computation to optimize the drug delivery to target sites and the treatment efficacy

Causal and associational language in observational health research: a systematic evaluation

We estimated the degree to which language used in the high profile medical/public health/epidemiology literature implied causality using language linking exposures to outcomes and action recommendations; examined disconnects between language and recommendations; identified the most common linking phrases; and estimated how strongly linking phrases imply causality. We searched and screened for 1,170 articles from 18 high-profile journals (65 per journal) published from 2010-2019. Based on written framing and systematic guidance, three reviewers rated the degree of causality implied in abstracts and full text for exposure/outcome linking language and action recommendations. Reviewers rated the causal implication of exposure/outcome linking language as None (no causal implication) in 13.8%, Weak 34.2%, Moderate 33.2%, and Strong 18.7% of abstracts. The implied causality of action recommendations was higher than the implied causality of linking sentences for 44.5% or commensurate for 40.3% of articles. The most common linking word in abstracts was “associate” (45.7%). Reviewer’s ratings of linking word roots were highly heterogeneous; over half of reviewers rated “association” as having at least some causal implication. This research undercuts the assumption that avoiding “causal” words leads to clarity of interpretation in medical research

31st Annual Meeting and Associated Programs of the Society for Immunotherapy of Cancer (SITC 2016) : part two

Background The immunological escape of tumors represents one of the main ob- stacles to the treatment of malignancies. The blockade of PD-1 or CTLA-4 receptors represented a milestone in the history of immunotherapy. However, immune checkpoint inhibitors seem to be effective in specific cohorts of patients. It has been proposed that their efficacy relies on the presence of an immunological response. Thus, we hypothesized that disruption of the PD-L1/PD-1 axis would synergize with our oncolytic vaccine platform PeptiCRAd. Methods We used murine B16OVA in vivo tumor models and flow cytometry analysis to investigate the immunological background. Results First, we found that high-burden B16OVA tumors were refractory to combination immunotherapy. However, with a more aggressive schedule, tumors with a lower burden were more susceptible to the combination of PeptiCRAd and PD-L1 blockade. The therapy signifi- cantly increased the median survival of mice (Fig. 7). Interestingly, the reduced growth of contralaterally injected B16F10 cells sug- gested the presence of a long lasting immunological memory also against non-targeted antigens. Concerning the functional state of tumor infiltrating lymphocytes (TILs), we found that all the immune therapies would enhance the percentage of activated (PD-1pos TIM- 3neg) T lymphocytes and reduce the amount of exhausted (PD-1pos TIM-3pos) cells compared to placebo. As expected, we found that PeptiCRAd monotherapy could increase the number of antigen spe- cific CD8+ T cells compared to other treatments. However, only the combination with PD-L1 blockade could significantly increase the ra- tio between activated and exhausted pentamer positive cells (p= 0.0058), suggesting that by disrupting the PD-1/PD-L1 axis we could decrease the amount of dysfunctional antigen specific T cells. We ob- served that the anatomical location deeply influenced the state of CD4+ and CD8+ T lymphocytes. In fact, TIM-3 expression was in- creased by 2 fold on TILs compared to splenic and lymphoid T cells. In the CD8+ compartment, the expression of PD-1 on the surface seemed to be restricted to the tumor micro-environment, while CD4 + T cells had a high expression of PD-1 also in lymphoid organs. Interestingly, we found that the levels of PD-1 were significantly higher on CD8+ T cells than on CD4+ T cells into the tumor micro- environment (p < 0.0001). Conclusions In conclusion, we demonstrated that the efficacy of immune check- point inhibitors might be strongly enhanced by their combination with cancer vaccines. PeptiCRAd was able to increase the number of antigen-specific T cells and PD-L1 blockade prevented their exhaus- tion, resulting in long-lasting immunological memory and increased median survival

Multi-scale effects of nutrition on an arboreal folivore

Habitat loss is a leading cause of decline in animal populations and identifying suitable habitats are essential for the conservation and management of wildlife. Our ability to identify suitable habitats is reliant on our understanding of the factors that influence the expansion, persistence and loss of animal populations. Nutrition underpins animal growth and reproductive success and is therefore a key factor in animal population dynamics. Both nutrients and anti-feedant secondary metabolites affect the feeding behaviour of folivores such as the koala at local scales. How this translates to whole landscapes remains unknown in any system. I suspect that the availability of plant nutrients and secondary metabolites varies across large Australian forest landscapes, which would explain why there are islands of suitable habitat in a sea of uninhabitable forest. Our understanding of how nutrition regulates herbivore population density is limited by our ability to collect plant chemistry data across landscapes. This typically involves the collection and analysis of hundreds and thousands of plant samples. Two global near infrared calibration models to predict forage quality across large landscapes in an extensive dataset are introduced in Chapter one. Two biologically-relevant nutritional traits were predicted, available nitrogen (NA) and formylated phloroglucinol compounds (FPCs). I discuss techniques for developing robust predictive models, facilitating the integration of forage quality into landscape ecology. In Chapter two, I examined the role of nutrition in explaining the striking differences in koala population densities across its extensive range of habitats. I travelled across the wide distribution of the koala to collect the largest collection of eucalypt leaves for forage quality analysis. I found that forage quality explained variation in transcontinental patterns in herbivore population densities. There was a positive association of nitrogen (as proxies for protein) traits and a negative association of FPCs with koala density. Further, the effect of nutrition remained significant even when other environmental/landscape/climatic variables were accounted for in the model. To my knowledge, this was the first study to show how the effects of nutrition on animal populations can scale up to large landscapes. In Chapter three, I examined changes in forage quality to describe the cascading negative effects of disturbance on a vulnerable animal population. Following intensive logging and/or wildfires, Eucalyptus sieberi dominate the landscape and replace what was once a heterogeneous forest. I combined two large datasets, an large field survey of koala activity, and an extensive forage quality data set. I found that koalas were highly unlikely to be found in these E. sieberi dominated (i.e. intensely disturbed) forests. Further, the nutritional quality of forage quality of E. sieberi was the poorest of the eucalypt species sampled in the area, with very low concentrations of NA, and extremely high concentrations of unsubstituted B-ring flavanones (an herbivore-deterrent PSM specific to Monocalyptus species). I then demonstrated the process by which disturbance alters the suitability of habitat through changes in forage quality. I simulated the change in tree species composition, from heterogenous forest to E. sieberi and showed that forests dominated by E. sieberi are nutritionally-poor and unlikely to be suitable habitat for the koala. In Chapter four, I described how variation in plant chemistry can inspire baffling bark-eating behaviour in a “fussy leaf eater”. Koalas in the Monaro region of New South Wales, Australia eat bark from select individuals of a single species, E. mannifera. I revealed that the bark from these chewed trees were significantly higher in sodium and proposed that this remarkable feeding strategy has aided the persistence of a folivore in an otherwise mineral-poor environment. Further, I highlighted that the availability of sodium decreases increasing elevation above sea level and discussed the implications of these findings for the future conservation and management of this iconic animal. In this thesis, I explore the multi-scale effects of forage quality on an iconic, yet vulnerable specialist folivore, the koala. Each study contributes to our understanding of animal population requirements and we can use this information for effective conservation planning of wildlife populations

Whole-body protein turnover reveals the cost of detoxification of secondary metabolites in a vertebrate browser

The detoxification limitation hypothesis predicts that the metabolism and biotransformation of plant secondary metabolites (PSMs) elicit a cost to herbivores. There have been many attempts to estimate these costs to mammalian herbivores in terms of energ