Designing a broad-spectrum integrative approach for cancer prevention and treatment

Targeted therapies and the consequent adoption of "personalized" oncology have achieved notablesuccesses in some cancers; however, significant problems remain with this approach. Many targetedtherapies are highly toxic, costs are extremely high, and most patients experience relapse after a fewdisease-free months. Relapses arise from genetic heterogeneity in tumors, which harbor therapy-resistantimmortalized cells that have adopted alternate and compensatory pathways (i.e., pathways that are notreliant upon the same mechanisms as those which have been targeted). To address these limitations, aninternational task force of 180 scientists was assembled to explore the concept of a low-toxicity "broad-spectrum" therapeutic approach that could simultaneously target many key pathways and mechanisms. Using cancer hallmark phenotypes and the tumor microenvironment to account for the various aspectsof relevant cancer biology, interdisciplinary teams reviewed each hallmark area and nominated a widerange of high-priority targets (74 in total) that could be modified to improve patient outcomes. For thesetargets, corresponding low-toxicity therapeutic approaches were then suggested, many of which werephytochemicals. Proposed actions on each target and all of the approaches were further reviewed forknown effects on other hallmark areas and the tumor microenvironment. Potential contrary or procar-cinogenic effects were found for 3.9% of the relationships between targets and hallmarks, and mixedevidence of complementary and contrary relationships was found for 7.1%. Approximately 67% of therelationships revealed potentially complementary effects, and the remainder had no known relationship. Among the approaches, 1.1% had contrary, 2.8% had mixed and 62.1% had complementary relationships. These results suggest that a broad-spectrum approach should be feasible from a safety standpoint. Thisnovel approach has potential to be relatively inexpensive, it should help us address stages and types ofcancer that lack conventional treatment, and it may reduce relapse risks. A proposed agenda for futureresearch is offered

Uptake and depuration of PCB-153 in edible shrimp Palaemonetes varians and human health risk assessment

A medium-term mesocosm exposure study was conducted to elucidate bioaccumulation and depuration of polychlorinated biphenyl congener 153 (PCB-153) in edible shrimp Palaemonetes varians. Over the 15-day exposure period, shrimp under different exposure concentrations exhibited a significant increase in PCB153 concentration compared with control organisms. Distinct bioaccumulation patterns and uptake rates were observed depending on the exposure concentrations. For low PCB-153 exposure levels (0.25 μg L 1), accumulation followed a saturation model, reaching an apparent steady state after fifteen days exposure. For intermediate (2.5 μg L 1) and high PCB-153 levels (25 μg L 1), accumulation was faster and linear. In addition, the bioaccumulation rate was not proportional to PCB-153 concentration, and the bioaccumulation was higher at intermediate exposure concentrations. Regarding the depuration phase, P. varians lost up to 30% of PCB-153 after 72h and levels continued slowly to decrease until the end of the 30-d experimental period. However, PCB-153 levels in shrimp did not reach background values, and those exposed to moderate and high PCB-153 concentrations presented contamination levels much higher than the regulatory limit for human food consumption (75ngg 1 ww for Σ6 PCB).This research was supported by FCT (Fundação para a Ciência e Tecnologia) through a PhD grantat tributed to T. F. Grilo (SFRH/BD/ 44936/2008) and MERCOAST project (PTDC/MAR/101906/2008), with funds from POPH (Portuguese Operational Human Potential Program), QREN Portugal (Portuguese National Strategic Reference Framework), and MCTES (Portuguese Ministry of Science, Technology, and Higher Education). P. Pato acknowledges a post doctoral fellowship from FCT (SFRH/BPD/35068/2007)

Distribution-free exponentially weighted moving average control charts for monitoring unknown location

Distribution-free (nonparametric) control charts provide a robust alternative to a data analyst when there is lack of knowledge about the underlying distribution. A two-sided nonparametric Phase II exponentially weighted moving average (EWMA) control chart, based on the exceedance statistics (EWMA-EX), is proposed for detecting a shift in the location parameter of a continuous distribution. The nonparametric EWMA chart combines the advantages of a nonparametric control chart (known and robust in-control performance) with the better shift detection properties of an EWMA chart. Guidance and recommendations are provided for practical implementation of the chart along with illustrative examples. A performance comparison is made with the traditional (normal theory) EWMA chart for subgroup averages and a recently proposed nonparametric EWMA chart based on the Wilcoxon-Mann- Whitney statistics. A summary and some concluding remarks are given.http://www.elsevier.com/locate/csdanf201

Characterizing treatment pathways at scale using the OHDSI network

Observational research promises to complement experimental research by providing large, diverse populations that would be infeasible for an experiment. Observational research can test its own clinical hypotheses, and observational studies also can contribute to the design of experiments and inform the generalizability of experimental research. Understanding the diversity of populations and the variance in care is one component. In this study, the Observational Health Data Sciences and Informatics (OHDSI) collaboration created an international data network with 11 data sources from four countries, including electronic health records and administrative claims data on 250 million patients. All data were mapped to common data standards, patient privacy was maintained by using a distributed model, and results were aggregated centrally. Treatment pathways were elucidated for type 2 diabetes mellitus, hypertension, and depression. The pathways revealed that the world is moving toward more consistent therapy over time across diseases and across locations, but significant heterogeneity remains among sources, pointing to challenges in generalizing clinical trial results. Diabetes favored a single first-line medication, metformin, to a much greater extent than hypertension or depression. About 10% of diabetes and depression patients and almost 25% of hypertension patients followed a treatment pathway that was unique within the cohort. Aside from factors such as sample size and underlying population (academic medical center versus general population), electronic health records data and administrative claims data revealed similar results. Large-scale international observational research is feasible.George Hripcsak, Patrick B. Ryan, Jon D. Duke, Nigam H. Shah, Rae Woong Park, Vojtech Huser ... et al