ASU Scholarship Showcase

Many drugs are effective in the early stage of treatment, but patients develop drug resistance after a certain period of treatment, causing failure of the therapy. An important example is Herceptin, a popular monoclonal antibody drug for breast cancer by specifically targeting human epidermal growth factor receptor 2 (Her2). Here we demonstrate a quantitative binding kinetics analysis of drug-target interactions to investigate the molecular scale origin of drug resistance. Using a surface plasmon resonance imaging, we measured the in situ Herceptin-Her2 binding kinetics in single intact cancer cells for the first time, and observed significantly weakened Herceptin-Her2 interactions in Herceptin-resistant cells, compared to those in Herceptin-sensitive cells. We further showed that the steric hindrance of Mucin-4, a membrane protein, was responsible for the altered drug-receptor binding. This effect of a third molecule on drug-receptor interactions cannot be studied using traditional purified protein methods, demonstrating the importance of the present intact cell-based binding kinetics analysis.

At the end of the dark ages, anatomy was taught as though everything that could be known was known. Scholars learned about what had been discovered rather than how to make discoveries. This was true even though the body (and the rest of biology) was very poorly understood. The renaissance eventually brought a revolution in how scholars (and graduate students) were trained and worked. This revolution never occurred in K-12 or university education such that we now teach young students in much the way that scholars were taught in the dark ages, we teach them what is already known rather than the process of knowing. Citizen science offers a way to change K-12 and university education and, in doing so, complete the renaissance. Here we offer an example of such an approach and call for change in the way students are taught science, change that is more possible than it has ever been and is, nonetheless, five hundred years delayed.

Periodicities (repeating patterns) are observed in many human behaviors. Their strength may capture untapped patterns that incorporate sleep, sedentary, and active behaviors into a single metric indicative of better health. We present a framework to detect periodicities from longitudinal wrist-worn accelerometry data. GENEActiv accelerometer data were collected from 20 participants (17 men, 3 women, aged 35–65) continuously for 64.4±26.2 (range: 13.9 to 102.0) consecutive days. Cardiometabolic risk biomarkers and health-related quality of life metrics were assessed at baseline. Periodograms were constructed to determine patterns emergent from the accelerometer data. Periodicity strength was calculated using circular autocorrelations for time-lagged windows. The most notable periodicity was at 24 h, indicating a circadian rest-activity cycle; however, its strength varied significantly across participants. Periodicity strength was most consistently associated with LDL-cholesterol (r’s = 0.40–0.79, P’s < 0.05) and triglycerides (r’s = 0.68–0.86, P’s < 0.05) but also associated with hs-CRP and health-related quality of life, even after adjusting for demographics and self-rated physical activity and insomnia symptoms. Our framework demonstrates a new method for characterizing behavior patterns longitudinally which captures relationships between 24 h accelerometry data and health outcomes.

Despite recent progress in the uptake of evidence-based health promotion (EBHP) programs within communities, many factors contribute to the need to focus on dissemination. These include the growth in the aging population, health care resource limitations, and interests in preserving community-based opportunities for maintaining independence and maximizing quality of life. For these reasons, The Prevention Research Centers’ Healthy Aging Research Network (HAN), funded by the Centers for Disease Control and Prevention’s (CDC’s) Healthy Aging Program, has as its core mission, to translate effective healthy aging interventions into sustainable community-based programs. Researchers and community-based stakeholders collaborate across HAN’s seven member center and two affiliate universities (Figure 1) to develop and implement health promotion programs for older adults at individual, organizational, environmental, and policy levels (1–3). This commentary highlights selected HAN contributions to the EBHP movement from 2001 to 2014. These contributions serve as examples of potential models for future partnership efforts to enhance implementation, dissemination, and sustainability of EBHP programs.

Background: Falls are a major public health concern in older adults. Recent fall prevention guidelines recommend the use of multifactorial fall prevention programs (FPPs) that include exercise for community-dwelling older adults; however, the availability of sustainable, community-based FPPs is limited.

Methods: We conducted a 24-week quasi-experimental study to evaluate the efficacy of a community-based, multifactorial FPP [Stay in Balance (SIB)] on dynamic and functional balance and muscular strength. The SIB program was delivered by allied health students and included a health education program focused on fall risk factors and a progressive exercise program emphasizing lower-extremity strength and balance. All participants initially received the 12-week SIB program, and participants were non-randomly assigned at baseline to either continue the SIB exercise program at home or as a center-based program for an additional 12 weeks. Adults aged 60 and older (n = 69) who were at-risk of falling (fall history or 2+ fall risk factors) were recruited to participate. Mixed effects repeated measures using Statistical Application Software Proc Mixed were used to examine group, time, and group-by-time effects on dynamic balance (8-Foot Up and Go), functional balance (Berg Balance Scale), and muscular strength (30 s chair stands and 30 s arm curls). Non-normally distributed outcome variables were log-transformed.

Results: After adjusting for age, gender, and body mass index, 8-Foot Up and Go scores, improved significantly over time [F_(2,173) = 8.92, p = 0.0; T0 − T2 diff = 1.2 (1.0)]. Berg Balance Scores [F_(2,173) = 29.0, p < 0.0001; T0 − T2 diff = 4.96 (0.72)], chair stands [F_(2,171) = 10.17, p < 0.0001; T0 − T2 diff = 3.1 (0.7)], and arm curls [F_(2,171) = 12.7, p < 0.02; T0 − T2 diff = 2.7 (0.6)] also all improved significantly over time. There were no significant group-by-time effects observed for any of the outcomes.

Conclusion: The SIB program improved dynamic and functional balance and muscular strength in older adults at-risk for falling. Our findings indicate continuing home-based strength and balance exercises at home after completion of a center-based FPP program may be an effective and feasible way to maintain improvements in balance and strength parameters.

Functional magnetic resonance imaging (fMRI) has significant potential in the study and treatment of neurological disorders and stroke. Region of interest (ROI) analysis in such studies allows for testing of strong a priori clinical hypotheses with improved statistical power. A commonly used automated approach to ROI analysis is to spatially normalize each participant’s structural brain image to a template brain image and define ROIs using an atlas. However, in studies of individuals with structural brain lesions, such as stroke, the gold standard approach may be to manually hand-draw ROIs on each participant’s non-normalized structural brain image. Automated approaches to ROI analysis are faster and more standardized, yet are susceptible to preprocessing error (e.g., normalization error) that can be greater in lesioned brains. The manual approach to ROI analysis has high demand for time and expertise, but may provide a more accurate estimate of brain response. In this study, commonly used automated and manual approaches to ROI analysis were directly compared by reanalyzing data from a previously published hypothesis-driven cognitive fMRI study, involving individuals with stroke. The ROI evaluated is the pars opercularis of the inferior frontal gyrus. Significant differences were identified in task-related effect size and percent-activated voxels in this ROI between the automated and manual approaches to ROI analysis. Task interactions, however, were consistent across ROI analysis approaches. These findings support the use of automated approaches to ROI analysis in studies of lesioned brains, provided they employ a task interaction design.

The relationship between the neurobiology of speech and music has been investigated for more than a century. There remains no widespread agreement regarding how (or to what extent) music perception utilizes the neural circuitry that is engaged in speech processing, particularly at the cortical level. Prominent models such as Patel's Shared Syntactic Integration Resource Hypothesis (SSIRH) and Koelsch's neurocognitive model of music perception suggest a high degree of overlap, particularly in the frontal lobe, but also perhaps more distinct representations in the temporal lobe with hemispheric asymmetries. The present meta-analysis study used activation likelihood estimate analyses to identify the brain regions consistently activated for music as compared to speech across the functional neuroimaging (fMRI and PET) literature. Eighty music and 91 speech neuroimaging studies of healthy adult control subjects were analyzed. Peak activations reported in the music and speech studies were divided into four paradigm categories: passive listening, discrimination tasks, error/anomaly detection tasks and memory-related tasks. We then compared activation likelihood estimates within each category for music vs. speech, and each music condition with passive listening. We found that listening to music and to speech preferentially activate distinct temporo-parietal bilateral cortical networks. We also found music and speech to have shared resources in the left pars opercularis but speech-specific resources in the left pars triangularis. The extent to which music recruited speech-activated frontal resources was modulated by task. While there are certainly limitations to meta-analysis techniques particularly regarding sensitivity, this work suggests that the extent of shared resources between speech and music may be task-dependent and highlights the need to consider how task effects may be affecting conclusions regarding the neurobiology of speech and music.

Nucleic Acid Programmable Protein Arrays (NAPPA) have emerged as a powerful and innovative technology for the screening of biomarkers and the study of protein-protein interactions, among others possible applications. The principal advantages are the high specificity and sensitivity that this platform offers. Moreover, compared to conventional protein microarrays, NAPPA technology avoids the necessity of protein purification, which is expensive and time-consuming, by substituting expression in situ with an in vitro transcription/translation kit. In summary, NAPPA arrays have been broadly employed in different studies improving knowledge about diseases and responses to treatments. Here, we review the principal advances and applications performed using this platform during the last years.

Two distinct monocyte (Mo)/macrophage (Mp) subsets (Ly6C^low and Ly6C^hi) orchestrate cardiac recovery process following myocardial infarction (MI). Prostaglandin (PG) E₂ is involved in the Mo/Mp-mediated inflammatory response, however, the role of its receptors in Mos/Mps in cardiac healing remains to be determined. Here we show that pharmacological inhibition or gene ablation of the Ep3 receptor in mice suppresses accumulation of Ly6C^low Mos/Mps in infarcted hearts. Ep3 deletion in Mos/Mps markedly attenuates healing after MI by reducing neovascularization in peri-infarct zones. Ep3 deficiency diminishes CX3C chemokine receptor 1 (CX3CR1) expression and vascular endothelial growth factor (VEGF) secretion in Mos/Mps by suppressing TGFβ1 signaling and subsequently inhibits Ly6C^low Mos/Mps migration and angiogenesis. Targeted overexpression of Ep3 receptors in Mos/Mps improves wound healing by enhancing angiogenesis. Thus, the PGE₂/Ep3 axis promotes cardiac healing after MI by activating reparative Ly6C^low Mos/Mps, indicating that Ep3 receptor activation may be a promising therapeutic target for acute MI.