Missing data are common in statistical analyses, and imputation methods based on random forests (RF) are becoming popular for handling missing data especially in biomedical research. Unlike standard ...imputation approaches, RF-based imputation methods do not assume normality or require specification of parametric models. However, it is still inconclusive how they perform for non-normally distributed data or when there are non-linear relationships or interactions.
To examine the effects of these three factors, a variety of datasets were simulated with outcome-dependent missing at random (MAR) covariates, and the performances of the RF-based imputation methods missForest and CALIBERrfimpute were evaluated in comparison with predictive mean matching (PMM).
Both missForest and CALIBERrfimpute have high predictive accuracy but missForest can produce severely biased regression coefficient estimates and downward biased confidence interval coverages, especially for highly skewed variables in nonlinear models. CALIBERrfimpute typically outperforms missForest when estimating regression coefficients, although its biases are still substantial and can be worse than PMM for logistic regression relationships with interaction.
RF-based imputation, in particular missForest, should not be indiscriminately recommended as a panacea for imputing missing data, especially when data are highly skewed and/or outcome-dependent MAR. A correct analysis requires a careful critique of the missing data mechanism and the inter-relationships between the variables in the data.
Cell adhesion is an essential aspect of cellular behavior. Finding innovative methods to probe the adhesion of cells in their native state can greatly advance the understanding of control and ...regulation of cellular behavior and their impact on human health. The quartz crystal microbalance (QCM) is a label-free, biosensing system that has, in the past fifty years, evolved from a simple acoustic based mass sensor to a powerful bioanalytical tool. Its unique capability of monitoring the cell-substrate interaction non-invasively in real time has led to the emergence of its applications in areas that are relevant to fundamental cell biology and medical research. This review is intended to provide readers an overview of the use of the QCM for examination of cell-substrate adhesion. It also describes how this innovative approach can be extended to the study of other aspects of cellular behavior, such as cell morphology, cell mechanics, cell motility, cell signaling, all of which can potentially be applied to medical diagnosis and/or pharmaceutical development. In this review a major emphasis is placed on informing readers about some of the most important practical aspects of the QCM-based cell study including data acquisition and analysis, the substrate surface manipulation, and cell manipulation.
•Overview of the use of the QCM for examination of cell-substrate adhesion.•Discussion on how the QCM-based approach can be extended to the study of other aspects of cellular behavior.•Review of some of the most important practical aspects of the QCM-based cell study.
Advanced basal cell carcinomas (BCCs) frequently acquire resistance to Smoothened (SMO) inhibitors through unknown mechanisms. Here we identify SMO mutations in 50% (22 of 44) of resistant BCCs and ...show that these mutations maintain Hedgehog signaling in the presence of SMO inhibitors. Alterations include four ligand binding pocket mutations defining sites of inhibitor binding and four variants conferring constitutive activity and inhibitor resistance, illuminating pivotal residues that ensure receptor autoinhibition. In the presence of a SMO inhibitor, tumor cells containing either class of SMO mutants effectively outcompete cells containing the wild-type SMO. Finally, we show that both classes of SMO variants respond to aPKC-ι/λ or GLI2 inhibitors that operate downstream of SMO, setting the stage for the clinical use of GLI antagonists.
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•Functional SMO mutations are detected in the majority of SMO inhibitor-resistant BCCs•Resistance occurs by suppressing drug responsiveness and SMO autoinhibition•SMO mutants explain both intrinsic and acquired tumor resistance•Inhibition of aPKC-ι/λ or GLI2 bypasses SMO variants to suppress Hedgehog signaling
Atwood et al. identify key SMO mutations that confer resistance to SMO inhibitors in basal cell carcinomas (BCC) and show that these mutants respond to aPKC-ι/λ or GLI2 inhibitors, providing potential approaches for treating BCCs resistant to SMO inhibitors.
Alterations in hedgehog signaling are implicated in the pathogenesis of basal-cell carcinoma. Although most basal-cell carcinomas are treated surgically, no effective therapy exists for locally ...advanced or metastatic basal-cell carcinoma. A phase 1 study of vismodegib (GDC-0449), a first-in-class, small-molecule inhibitor of the hedgehog pathway, showed a 58% response rate among patients with advanced basal-cell carcinoma.
In this multicenter, international, two-cohort, nonrandomized study, we enrolled patients with metastatic basal-cell carcinoma and those with locally advanced basal-cell carcinoma who had inoperable disease or for whom surgery was inappropriate (because of multiple recurrences and a low likelihood of surgical cure, or substantial anticipated disfigurement). All patients received 150 mg of oral vismodegib daily. The primary end point was the independently assessed objective response rate; the primary hypotheses were that the response rate would be greater than 20% for patients with locally advanced basal-cell carcinoma and greater than 10% for those with metastatic basal-cell carcinoma.
In 33 patients with metastatic basal-cell carcinoma, the independently assessed response rate was 30% (95% confidence interval CI, 16 to 48; P=0.001). In 63 patients with locally advanced basal-cell carcinoma, the independently assessed response rate was 43% (95% CI, 31 to 56; P<0.001), with complete responses in 13 patients (21%). The median duration of response was 7.6 months in both cohorts. Adverse events occurring in more than 30% of patients were muscle spasms, alopecia, dysgeusia (taste disturbance), weight loss, and fatigue. Serious adverse events were reported in 25% of patients; seven deaths due to adverse events were noted.
Vismodegib is associated with tumor responses in patients with locally advanced or metastatic basal-cell carcinoma. (Funded by Genentech; Erivance BCC ClinicalTrials.gov number, NCT00833417.).
In 2010, the Institute of Education Sciences commissioned a much-needed national evaluation of response to intervention (RTI). The evaluators defined their task very narrowly, asking “Does the use of ...universal screening, including a cut-point for designating students for more intensive Tier 2 and Tier 3 interventions, increase children’s performance on a comprehensive reading measure?” Their regression-discontinuity analysis showed that first-grade children designated for (but not necessarily receiving) more intensive intervention in the 146 study schools performed significantly worse than children not designated for it. There were no reliable differences between designated and nondesignated students in Grades 2 or 3. The provocativeness of these findings notwithstanding, the evaluation’s focus and design weakens its importance. RTI implementation data were also collected in the 146 study schools. These data suggest many of them were not conducting RTI in a manner supported by research and policy. Such findings and others’ evaluations of RTI advance the idea that simpler frameworks may encourage more educators to implement RTI’s most important components with fidelity.
Bumble bees are globally important pollinators, contributing hundreds of millions of dollars annually in crop pollination services. Several species are in decline, making it paramount to understand ...how pathogens and nutrition shape bee health. Previous work has shown that consuming sunflower pollen (Helianthus annuus) dramatically reduces infection by the trypanosomatid gut pathogen, Crithidia bombi, in the common eastern bumble bee (Bombus impatiens). Sunflower pollen may therefore be useful as a dietary supplement for reducing this pathogen in managed bumble bee colonies. Here, we assessed the efficacy of freezer-stored sunflower pollen that was collected in different years and locations for reducing pathogen infection. We tested sunflower pollen that was 1, 3, 4, or 5 yr old and from sunflowers grown in the United States or China against a control of 1-yr-old buckwheat pollen from China, since buckwheat pollen results in high infection. We hypothesized that older pollen would have weaker medicinal effects due to degradation of pollen quality. We found that all sunflower pollen treatments significantly decreased Crithidia infection compared to controls. These results suggest that sunflower pollen can be freezer-stored for up to 5 yr and sourced from a wide range of geographic areas and still maintain its medicinal effects against Crithidia in the common eastern bumble bee. This is helpful information for stakeholders who might administer sunflower pollen as a dietary supplement to manage Crithidia in commercial bumble bee colonies.
In this introduction to this special issue, “A Decade Later,” we provide an overview of the accomplishments as well as the persistent questions surrounding RTI. We organize this discussion within 3 ...categories: assessment, instruction, and policy. Within each of these sections, we also highlight how the articles in the present special issue expand upon the key issues. Developed initially for the early grades (kindergarten through third grade) and primarily in the area of reading, many-although not all-of these issues speak to the expansion of RTI to address a broader set of academic content areas and the full range of grade levels.
To assess the tumor response to the smoothened (SMO) inhibitor, sonidegib (LDE225), in patients with an advanced basal cell carcinoma (BCC) resistant to treatment with vismodegib (GDC0449).
Nine ...patients with an advanced BCC that was previously resistant to treatment with vismodegib were given sonidegib in this investigational, open-label study. Tumor response was determined using the response evaluation criteria in solid tumors. SMO mutations were identified using biopsy samples from the target BCC location.
The median duration of treatment with sonidegib was 6 weeks (range, 3-58 weeks). Five patients experienced progressive disease with sonidegib. Three patients experienced stable disease and discontinued sonidegib either due to adverse events (n = 1) or due to election for surgery (n = 2). The response of one patient was not evaluable. SMO mutations with in vitro data suggesting resistance to Hh pathway inhibition were identified in 5 patients, and none of these patients experienced responses while on sonidegib.
Patients with advanced BCCs that were previously resistant to treatment with vismodegib similarly demonstrated treatment resistance with sonidegib. Patients who have developed treatment resistance to an SMO inhibitor may continue to experience tumor progression in response to other SMO inhibitors.
Several floral microbes are known to be pathogenic to plants or floral visitors such as pollinators. Despite the ecological and economic importance of pathogens deposited in flowers, we often lack a ...basic understanding of how floral traits influence disease transmission. Here, we provide the first systematic review regarding how floral traits attract vectors (for plant pathogens) or hosts (for animal pathogens), mediate disease establishment and evolve under complex interactions with plant mutualists that can be vectors for microbial antagonists. Attraction of floral visitors is influenced by numerous phenological, morphological and chemical traits, and several plant pathogens manipulate floral traits to attract vectors. There is rapidly growing interest in how floral secondary compounds and antimicrobial enzymes influence disease establishment in plant hosts. Similarly, new research suggests that consumption of floral secondary compounds can reduce pathogen loads in animal pollinators. Given recent concerns about pollinator declines caused in part by pathogens, the role of floral traits in mediating pathogen transmission is a key area for further research. We conclude by discussing important implications of floral transmission of pathogens for agriculture, conservation and human health, suggesting promising avenues for future research in both basic and applied biology.
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