CYberinfrastructure for COmparative effectiveness REsearch (CYCORE): improving data from cancer clinical trials

Improved approaches and methodologies are needed to conduct comparative effectiveness research (CER) in oncology. While cancer therapies continue to emerge at a rapid pace, the review, synthesis, and dissemination of evidence-based interventions across clinical trials lag in comparison. Rigorous and systematic testing of competing therapies has been clouded by age-old problems: poor patient adherence, inability to objectively measure the environmental influences on health, lack of knowledge about patients’ lifestyle behaviors that may affect cancer’s progression and recurrence, and limited ability to compile and interpret the wide range of variables that must be considered in the cancer treatment. This lack of data integration limits the potential for patients and clinicians to engage in fully informed decision-making regarding cancer prevention, treatment, and survivorship care, and the translation of research results into mainstream medical care. Particularly important, as noted in a 2009 report on CER to the President and Congress, the limited focus on health behavior-change interventions was a major hindrance in this research landscape (DHHS 2009). This paper describes an initiative to improve CER for cancer by addressing several of these limitations. The Cyberinfrastructure for Comparative Effectiveness Research (CYCORE) project, informed by the National Science Foundation’s 2007 report “Cyberinfrastructure Vision for 21st Century Discovery” has, as its central aim, the creation of a prototype for a user-friendly, open-source cyberinfrastructure (CI) that supports acquisition, storage, visualization, analysis, and sharing of data important for cancer-related CER. Although still under development, the process of gathering requirements for CYCORE has revealed new ways in which CI design can significantly improve the collection and analysis of a wide variety of data types, and has resulted in new and important partnerships among cancer researchers engaged in advancing health-related CI

Classification of HCV NS5B Polymerase Inhibitors Using Support Vector Machine

Using a support vector machine (SVM), three classification models were built to predict whether a compound is an active or weakly active inhibitor based on a dataset of 386 hepatitis C virus (HCV) NS5B polymerase NNIs (non-nucleoside analogue inhibitors) fitting into the pocket of the NNI III binding site. For each molecule, global descriptors, 2D and 3D property autocorrelation descriptors were calculated from the program ADRIANA.Code. Three models were developed with the combination of different types of descriptors. Model 2 based on 16 global and 2D autocorrelation descriptors gave the highest prediction accuracy of 88.24% and MCC (Matthews correlation coefficient) of 0.789 on test set. Model 1 based on 13 global descriptors showed the highest prediction accuracy of 86.25% and MCC of 0.732 on external test set (including 80 compounds). Some molecular properties such as molecular shape descriptors (InertiaZ, InertiaX and Span), number of rotatable bonds (NRotBond), water solubility (LogS), and hydrogen bonding related descriptors performed important roles in the interactions between the ligand and NS5B polymerase

Ultrasensitive plano-concave optical microresonators for ultrasound sensing

Highly sensitive broadband ultrasound detectors are needed to expand the capabilities of biomedical ultrasound, photoacoustic imaging and industrial ultrasonic non-destructive testing techniques. Here, a generic optical ultrasound sensing concept based on a novel plano-concave polymer microresonator is described. This achieves strong optical confinement (Q-factors > 105) resulting in very high sensitivity with excellent broadband acoustic frequency response and wide directivity. The concept is highly scalable in terms of bandwidth and sensitivity. To illustrate this, a family of microresonator sensors with broadband acoustic responses up to 40 MHz and noise-equivalent pressures as low as 1.6 mPa per √Hz have been fabricated and comprehensively characterized in terms of their acoustic performance. In addition, their practical application to high-resolution photoacoustic and ultrasound imaging is demonstrated. The favourable acoustic performance and design flexibility of the technology offers new opportunities to advance biomedical and industrial ultrasound-based techniques

RNase 7 Contributes to the Cutaneous Defense against Enterococcus faecium

Background: Human skin is able to mount a fast response against invading microorganisms by the release of antimicrobial proteins such as the ribonuclease RNase 7. Because RNase 7 exhibits high activity against Enterococcus faecium the aim of this study was to further explore the role of RNase 7 in the cutaneous innate defense system against E. faecium. Methodology/Principal Findings: Absolute quantification using real-time PCR and ELISA revealed that primary keratinocytes expressed high levels of RNase 7. Immunohistochemistry showed RNase 7 expression in all epidermal layers of the skin with an intensification in the upper more differentiated layers. Furthermore, RNase 7 was secreted by keratinocytes in vitro and in vivo in a site-dependent way. RNase 7 was still active against E. faecium at low pH (5.5) or high NaCl (150 mM) concentration and the bactericidal activity of RNase 7 against E. faecium required no ribonuclease activity as shown by recombinant RNase 7 lacking enzymatic activity. To further explore the role of RNase 7 in cutaneous defense against E. faecium, we investigated whether RNase 7 contributes to the E. faecium killing activity of skin extracts derived from stratum corneum. Treatment of the skin extract with an RNase 7 specific antibody, which neutralizes the antimicrobial activity of RNase 7, diminished its E. faecium killing activity. Conclusions/Significance: Our data indicate that RNase 7 contributes to the E. faecium-killing activity of skin extracts an

Effects of nutrient addition and soil drainage on germination of N-fixing and non-N-fixing tropical dry forest tree species

To develop generalised predictions regarding the effects of atmospheric nitrogen (N) and phosphorus (P) deposition on vegetation communities, it is necessary to account for the impacts of increased nutrient availability on the early life history stages of plants. Additionally, it is important to determine if these responses (a) differ between plant functional groups and (b) are modulated by soil drainage, which may affect the persistence of added nutrients. We experimentally assessed seed germination responses (germination proportion and germination energy, i.e. time to germination) of commonly occurring N-fixing and non-N-fixing tropical dry forest tree species found in India to simulated N and P deposition in well-drained soils, as well as soils with impeded drainage. When soils were not allowed to drain, germination proportion declined with nutrient addition, while germination energy remained unchanged. Stronger declines in germination proportion were observed for N-fixing species. In free-draining soils, nutrient addition did not affect germination proportion in either functional group. However, we detected a trend of delayed germination with nutrient addition, especially in N-fixers. Our results suggest that nutrient deposition can lead to potential shifts in functional dominance and tree community composition of tropical dry forests in the long term through its effects on early life stages of trees, although the mechanisms underlying the observed germination responses remain unclear. Further, such effects are likely to be spatially variable across the geographic range in which tropical dry forests occur depending on soil drainage properties

Parents’ Promotion of Psychological Autonomy, Psychological Control, and Mexican–American Adolescents’ Adjustment

Mexican–American adolescents are at an elevated risk for adjustment difficulties. In an effort to identify parenting practices that can affect the adjustment of Mexican–American youth, the current study examined parents’ promotion of psychological autonomy and parents’ psychological control as perceived by Mexican–American early adolescents, and explored their associations with adolescents’ adjustment in the context of acculturation. In 5th grade, 134 (54.5% female) Mexican–American adolescents reported on their acculturation level and the parenting practices of their mothers and fathers. In 5th and 7th grade, adolescents also reported on their depressive symptoms, number of delinquent friends, and self-worth. Perceptions of promotion of psychological autonomy and of psychological control were positively correlated. However, perceptions of more promotion of psychological autonomy and of less psychological control predicted fewer depressive symptoms 2 years later. Perceptions of more promotion of psychological autonomy also predicted fewer delinquent friends two years later. Finally, perceptions of more promotion of psychological autonomy predicted higher self-worth only among less acculturated adolescents. The study underscores the roles that promotion of psychological autonomy and psychological control may play in Mexican–American children’s well-being during early adolescence

Guidelines for the use and interpretation of assays for monitoring autophagy (4th edition)1.

In 2008, we published the first set of guidelines for standardizing research in autophagy. Since then, this topic has received increasing attention, and many scientists have entered the field. Our knowledge base and relevant new technologies have also been expanding. Thus, it is important to formulate on a regular basis updated guidelines for monitoring autophagy in different organisms. Despite numerous reviews, there continues to be confusion regarding acceptable methods to evaluate autophagy, especially in multicellular eukaryotes. Here, we present a set of guidelines for investigators to select and interpret methods to examine autophagy and related processes, and for reviewers to provide realistic and reasonable critiques of reports that are focused on these processes. These guidelines are not meant to be a dogmatic set of rules, because the appropriateness of any assay largely depends on the question being asked and the system being used. Moreover, no individual assay is perfect for every situation, calling for the use of multiple techniques to properly monitor autophagy in each experimental setting. Finally, several core components of the autophagy machinery have been implicated in distinct autophagic processes (canonical and noncanonical autophagy), implying that genetic approaches to block autophagy should rely on targeting two or more autophagy-related genes that ideally participate in distinct steps of the pathway. Along similar lines, because multiple proteins involved in autophagy also regulate other cellular pathways including apoptosis, not all of them can be used as a specific marker for bona fide autophagic responses. Here, we critically discuss current methods of assessing autophagy and the information they can, or cannot, provide. Our ultimate goal is to encourage intellectual and technical innovation in the field

Re-examining HSPC1 inhibitors

© 2017, The Author(s). HSPC1 is a critical protein in cancer development and progression, including colorectal cancer (CRC). However, clinical trial data reporting the effectiveness of HSPC1 inhibitors on several cancer types has not been as successful as predicted. Furthermore, some N-terminal inhibitors appear to be much more successful than others despite similar underlying mechanisms. This study involved the application of three N-terminal HSPC1 inhibitors, 17-DMAG, NVP-AUY922 and NVP-HSP990 on CRC cells. The effects on client protein levels over time were examined. HSPC1 inhibitors were also applied in combination with chemotherapeutic agents commonly used in CRC treatment (5-fluorouracil, oxaliplatin and irinotecan). As HSPA1A and HSPB1 have anti-apoptotic activity, gene-silencing techniques were employed to investigate the significance of these proteins in HSPC1 inhibitor and chemotherapeutic agent resistance. When comparing the action of the three HSPC1 inhibitors, there are distinct differences in the time course of important client protein degradation events. The differences between HSPC1 inhibitors were also reflected in combination treatment—17-DMAG was more effective compared with NVP-AUY922 in potentiating the cytotoxic effects of 5-fluorouracil, oxaliplatin and irinotecan. This study concludes that there are distinct differences between N-terminal HSPC1 inhibitors, despite their common mode of action. Although treatment with each of the inhibitors results in significant induction of the anti-apoptotic proteins HSPA1A and HSPB1, sensitivity to HSPC1 inhibitors is not improved by gene silencing of HSPA1A or HSPB1. HSPC1 inhibitors potentiate the cytotoxic effects of chemotherapeutic agents in CRC, and this approach is readily available to enter clinical trials. From a translational point of view, there may be great variability in sensitivity to the inhibitors between individual patients

Perspectives from the NanoSafety Modelling Cluster on the validation criteria for (Q)SAR models used in nanotechnology

Nanotechnology and the production of nanomaterials have been expanding rapidly in recent years. Since many types of engineered nanoparticles are suspected to be toxic to living organisms and to have a negative impact on the environment, the process of designing new nanoparticles and their applications must be accompanied by a thorough exposure risk analysis. (Quantitative) Structure-Activity Relationship ([Q]SAR) modelling creates promising options among the available methods for the risk assessment. These in silico models can be used to predict a variety of properties, including the toxicity of newly designed nanoparticles. However, (Q)SAR models must be appropriately validated to ensure the clarity, consistency and reliability of predictions. This paper is a joint initiative from recently completed European research projects focused on developing (Q)SAR methodology for nanomaterials. The aim was to interpret and expand the guidance for the well-known “OECD Principles for the Validation, for Regulatory Purposes, of (Q)SAR Models”, with reference to nano-(Q)SAR, and present our opinions on the criteria to be fulfilled for models developed for nanoparticles