New Insights into the Tumor Microenvironment Utilizing Protein Array Technology.

The tumor microenvironment (TME) is a considerably heterogeneous niche, which is created by tumor cells, the surrounding tumor stroma, blood vessels, infiltrating immune cells, and a variety of associated stromal cells. Intercellular communication within this niche is driven by soluble proteins synthesized by local tumor and stromal cells and include chemokines, growth factors, interferons, interleukins, and angiogenic factors. The interaction of tumor cells with their microenvironment is essential for tumorigenesis, tumor progression, growth, and metastasis, and resistance to drug therapy. Protein arrays enable the parallel detection of hundreds of proteins in a small amount of biological sample. Recent data have demonstrated that the application of protein arrays may yield valuable information regarding the structure and functional mechanisms of the TME. In this review, we will discuss protein array technologies and their applications in TME analysis to discern pathways involved in promoting the tumorigenic phenotype.

Tumor-induced perturbations of cytokines and immune cell networks.

Until recently, the intrinsically high level of cross-talk between immune cells, the complexity of immune cell development, and the pleiotropic nature of cytokine signaling have hampered progress in understanding the mechanisms of immunosuppression by which tumor cells circumvent native and adaptive immune responses. One technology that has helped to shed light on this complex signaling network is the cytokine antibody array, which facilitates simultaneous screening of dozens to hundreds of secreted signal proteins in complex biological samples. The combined applications of traditional methods of molecular and cell biology with the high-content, high-throughput screening capabilities of cytokine antibody arrays and other multiplexed immunoassays have revealed a complex mechanism that involves multiple cytokine signals contributed not just by tumor cells but by stromal cells and a wide spectrum of immune cell types. This review will summarize the interactions among cancerous and immune cell types, as well as the key cytokine signals that are required for tumors to survive immunoediting in a dormant state or to grow and spread by escaping it. Additionally, it will present examples of how probing secreted cell-cell signal networks in the tumor microenvironment (TME) with cytokine screens have contributed to our current understanding of these processes and discuss the implications of this understanding to antitumor therapies.

Antimicrobial use practices and opinions of beef farmers in England and Wales.

BACKGROUND: Limited research exists on antimicrobial use practices of beef farmers. This study aimed to investigate antimicrobial practices and perceptions of beef farmers in England and Wales, and identify drivers of higher antimicrobial use for treatment of bovine pneumonia. METHODS: A survey was sent out in 2017 to beef farmers in England and Wales who supply to two abattoirs. Descriptive statistics were used to summarise the data. A logistic regression model was built to determine factors associated with treating greater than 5 per cent of the predominant group in the herd with antimicrobials for pneumonia. RESULTS: There were a total of 171 useable responses. Most farmers reported using antimicrobials in less than 5 per cent of their herd for the treatment of common diseases. Most farmers (90 per cent) reported that they understood what antimicrobial resistance means, but only 55 per cent were aware of critically important antimicrobials and 9 per cent could name at least one critically important antimicrobial. Having a calf-rearing enterprise and not considering Johne's disease when buying in cattle were associated with using antimicrobials to treat pneumonia in greater than 5 per cent of the predominant group in the herd. CONCLUSION: Self-reported antimicrobial use appears to be low in beef farms. However, some gaps in understanding aspects of antimicrobial stewardship by farmers were identified.

Medical applications of nanoparticles and nanomaterials.

Current clinical diagnostics and therapeutics platforms are often limited by borderline sensitivity or efficacy levels. These limitations result from low or minimal specificity for the intended target cell or organ, span a multitude of physiological disorders and result in nominal success rates for diagnosis or treatment in many cases. Diagnosis and treatment of diseases such as cancer or viral infections require next generation medical methods. Nanotechnology has the potential to significantly address diagnostics and therapeutics sensitivity and resulting unwanted side effects by providing extremely precise reagents and tools that allow for unparalleled detection and treatment at the clinical level. This is accomplished through extremely controlled nanofabrication methodologies which result in the generation of molecularly defined nanoscale materials and devices that harbor known physical properties unique to each material in question and useful for particular medical applications. The further precise targeting of these materials to specific sites within the body allows for an added layer of accuracy and potency. Research in this area is quickly advancing to the point of providing a comprehensive portfolio of nanotechnology-based diagnostic and therapeutic platforms that will be unparalleled in sensitivity, specificity and elimination of unwanted side effects.

Quantitative proteomic analyses in blood: A window to human health and disease.

This review discusses how the measurement of proteins in blood and its components via quantitative proteomics analyses can inform health status. Various external and internal factors such as environmental conditions, genetic background, nutrition, diet, and lifestyle, chronic pathological conditions, disease state, or therapeutic intervention will be investigated and their effects on the protein profile will be shown. The resulting changes to ones' health and how this protein expression information can be used in early screening/diagnostic applications, drug discovery, precision treatment, patient management, and monitoring overall health status will also be presented.

Signaling and transcriptional control of pituitary development.

Many common morphogenic, signaling and transcriptional hierarchy themes exist with respect to a number of different model systems representing mammalian organogenesis. The developing pituitary gland defines a fundamentally ideal system for the study and classification of biochemical and molecular events associated with biological transitions such as organ and cellular positional determination as well as lineage-specific terminal differentiation. Recent advances in defining the extrinsic and intrinsic biological cascades behind pituitary development have shed light on the crosstalk between signaling molecules and transcription factors as well as the combinatorial regulatory codes guiding gland maturation. A thorough assessment of these codes is critical to a comprehensive understanding of pituitary organogenesis and the mechanisms which may go awry during tumorigenesis.

Cancer Stem Cell Biomarker Discovery Using Antibody Array Technology.

Cancer is a complex disease involving hundreds of pathways and numerous levels of disease progression. In addition, there is a growing body of evidence that the origins and growth rates of specific types of cancer may involve "cancer stem cells," which are defined as "cells within a tumor that possess the capacity to self-renew and to cause the development of heterogeneous lineages of cancer cells that comprise the tumor.(1)" Many types of cancer are now thought to harbor cancer stem cells. These cells themselves are thought to be unique in comparison to other cells types present within the tumor and to exhibit characteristics that allow for the promotion of tumorigenesis and in some cases metastasis. In addition, it is speculated that each type of cancer stem cell exhibits a unique set of molecular and biochemical markers. These markers, alone or in combination, may act as a signature for defining not only the type of cancer but also the progressive state. These biomarkers may also double as signaling entities which act autonomously or upon neighboring cancer stem cells or other cells within the local microenvironment to promote tumorigenesis. This review describes the heterogeneic properties of cancer stem cells and outlines the identification and application of biomarkers and signaling molecules defining these cells as they relate to different forms of cancer. Other examples of biomarkers and signaling molecules expressed by neighboring cells in the local tumor microenvironment are also discussed. In addition, biochemical signatures for cancer stem cell autocrine/paracrine signaling, local site recruitment, tumorigenic potential, and conversion to a stem-like phenotype are described.

Antibody arrays in biomarker discovery.

All of life is regulated by complex and organized chemical reactions that help dictate when to grow, to move, to reproduce, and to die. When these processes go awry, or are interrupted by pathological agents, diseases such as cancer, autoimmunity, or infections can result. Cytokines, chemokines, growth factors, adipokines, and other chemical moieties make up a vast subset of these chemical reactions that are altered in disease states, and monitoring changes in these molecules could provide for the identification of disease biomarkers. From the first identification of carcinoembryonic antigen, to the discovery of prostate-specific antigen, to numerous others described within, biomarkers of disease are detectable in a plethora of sample types. The growing number of biomarkers for infection, autoimmunity, and cancer allow for increasingly early detection, to identification of novel drug targets, to prognostic indicators of disease outcome. However, more and more studies are finding that a single cytokine or growth factor is insufficient as a true disease biomarker and that a more global perspective is needed to understand true disease biology. Such a broad view requires a multiplexed platform for chemical detection, and antibody arrays meet and exceed this need by performing this detection in a high-throughput fashion. Herein, we will discuss how antibody arrays have evolved, and how they have helped direct new drug target design, helped identify therapeutic disease markers, and helped in earlier disease detection. From asthma to renal disease, and neurological dysfunction to immunologic disorders, antibody arrays afford a bright future for new biomarkers discovery.

Evaluating the impact of an educational intervention on documentation of decision-making capacity in an emergency medical services system.

OBJECTIVES: To compare the documentation of decision-making capacity by advanced life support (ALS) providers and signature acquisition before, one month after, and one year after an educational intervention. METHODS: The intervention comprised a one-and-a-half-hour module on assessment and documentation of decision-making capacity. Ambulance call reports were reviewed for all ALS calls occurring during three two-month periods, and refusals of transport were recorded. Provider compliance with documentation of decision-making capacity and signature acquisition were determined from a convenience sample of 75 reports from each period. Reviewers were blinded to study period. Twenty-percent double data entry was undertaken to evaluate accuracy. Ninety-five percent confidence intervals were calculated to compare frequencies of cancelled calls and documentation. RESULTS: From the emergency medical services database, 7,744 calls before the intervention, 7,444 immediately after, and 7,604 one year later were identified. Documentation rates in the second and third periods did not differ from that prior to the intervention (1.3% vs. 0.0% and 0.0% in subsequent periods), nor did the rates of signature acquisition differ (85.3% vs. 85.3% and 78.6%). The accuracy of data entry was 92.6%. However, the frequency of call refusals decreased significantly after the intervention (from 9.0% to 2.0% and 6.6% in the respective periods). CONCLUSIONS: An educational intervention resulted in no change in the rate of decision-making capacity documentation or signature acquisition by ALS providers for refusal of transport. There was a temporary increase in the number of transported patients.

Patient safety in emergency medical services: executive summary and recommendations from the Niagara Summit.

Emergency medical services (EMS) personnel care for patients in challenging and dynamic environments that may contribute to an increased risk for adverse events. However, little is known about the risks to patient safety in the EMS setting. To address this knowledge gap, we conducted a systematic review of the literature, including nonrandomized, noncontrolled studies, conducted qualitative interviews of key informants, and, with the assistance of a pan-Canadian advisory board, hosted a 1-day summit of 52 experts in the field of EMS patient safety. The intent of the summit was to review available research, discuss the issues affecting prehospital patient safety, and discuss interventions that might improve the safety of the EMS industry. The primary objective was to define the strategic goals for improving patient safety in EMS. Participants represented all geographic regions of Canada and included administrators, educators, physicians, researchers, and patient safety experts. Data were collected through electronic voting and qualitative analysis of the discussions. The group reached consensus on nine recommendations to increase awareness, reduce adverse events, and suggest research and educational directions in EMS patient safety: increasing awareness of patient safety principles, improving adverse event reporting through creating nonpunitive reporting systems, supporting paramedic clinical decision making through improved research and education, policy changes, using flexible algorithms, adopting patient safety strategies from other disciplines, increasing funding for research in patient safety, salary support for paramedic researchers, and access to graduate training in prehospital research.