Serial Diffusion MRI to Monitor and Model Treatment Response of the Targeted Nanotherapy CRLX101

Purpose: Targeted nanotherapies are being developed to improve tumor drug delivery and enhance therapeutic response. Techniques that can predict response will facilitate clinical translation and may help define optimal treatment strategies. We evaluated the efficacy of diffusion-weighted magnetic resonance imaging to monitor early response to CRLX101 (a cyclodextrin-based polymer particle containing the DNA topoisomerase I inhibitor camptothecin) nanotherapy (formerly IT-101), and explored its potential as a therapeutic response predictor using a mechanistic model of tumor cell proliferation. Experimental Design: Diffusion MRI was serially conducted following CRLX101 administration in a mouse lymphoma model. Apparent diffusion coefficients (ADCs) extracted from the data were used as treatment response biomarkers. Animals treated with irinotecan (CPT-11) and saline were imaged for comparison. ADC data were also input into a mathematical model of tumor growth. Histological analysis using cleaved-caspase 3, terminal deoxynucleotidyl transferase–mediated dUTP nick end labeling, Ki-67, and hematoxylin and eosin (H&E) were conducted on tumor samples for correlation with imaging results. Results: CRLX101-treated tumors at day 2, 4, and 7 posttreatment exhibited changes in mean ADC = 16 ± 9%, 24 ± 10%, 49 ± 17%, and size (TV) = −5 ± 3%, −30 ± 4%, and −45 ± 13%, respectively. Both parameters were statistically greater than controls [p(ADC) ≤ 0.02, and p(TV) ≤ 0.01 at day 4 and 7], and noticeably greater than CPT-11–treated tumors (ADC = 5 ± 5%, 14 ± 7%, and 18 ± 6%; TV = −15 ± 5%, −22 ± 13%, and −26 ± 8%). Model-derived parameters for cell proliferation obtained using ADC data distinguished CRLX101-treated tumors from controls (P = 0.02). Conclusions: Temporal changes in ADC specified early CRLX101 treatment response and could be used to model image-derived cell proliferation rates following treatment. Comparisons of targeted and nontargeted treatments highlight the utility of noninvasive imaging and modeling to evaluate, monitor, and predict responses to targeted nanotherapeutics

Exercise-based interventions to enhance long-term sustainability of physical activity in older adults: a systematic review and meta-analysis of randomized clinical trials

Older adults; Physical activity; AdherenceAdultos mayores; Actividad física; AdherenciaAdults majors; Activitat física; AdherènciaExercise is a form of physical activity (PA). PA is an important marker of health and quality of life in older adults. The purpose of this study was to conduct a systematic review of the literature to assess the effect of exercise-based interventions on an at least six-month follow up PA measure, and to describe the specific strategies implemented during the intervention to strengthen the sustainability of PA in community-dwelling 65+ year-old adults. We registered and conducted a systematic review and meta-analysis (PROSPERO: CRD42017070892) of randomized clinical trials (RCT). We searched three electronic databases during January 2018 to identify RCT assessing any type of exercise-based intervention. Studies had to report a pre-, post-, and at least 6-month post-intervention follow-up. To be included, at least one PA outcome had to be assessed. The effect of exercise-based interventions was assessed compared to active (e.g., a low-intensity type of exercise, such as stretching or toning activities) and non-active (e.g., usual care) control interventions at several time points. Secondary analyses were conducted, restricted to studies that reported specific strategies to enhance the sustainability of PA. The intervention effect was measured on self-reported and objective measures of time spent in PA, by means of standardized mean differences. Standardized mean differences of PA level were pooled. Pooled estimates of effect were computed with the DerSimonian–Laird method, applying a random effects model. The risk of bias was also assessed. We included 12 studies, comparing 18 exercise intervention groups to four active and nine non-active control groups. Nine studies reported specific strategies to enhance the long-term sustainability of PA. The strategies were mostly related to the self-efficacy, self-control, and behavior capability principles based on the social cognitive theory. Exercise interventions compared to active control showed inconclusive and heterogeneous results. When compared to non-active control, exercise interventions improved PA time at the six-months follow up (standardized mean difference (SMD) 0.30; 95%CI 0.15 to 0.44; four studies; 724 participants; I2 0%), but not at the one- or two-years follow-ups. No data were available on the mid- and long-term effect of adding strategies to enhance the sustainability of PA. Exercise interventions have small clinical benefits on PA levels in community-dwelling older adults, with a decline in the observed improvement after six months of the intervention cessation.The present study was funded by United States Department of Health & Human Services National Institutes of Health (NIH), USA, and NIH National Institute on Aging (NIA), USA, (K24 AG057728)

Stance time variability and energy cost of walking in older adults

Purpose: To investigate differences in gait characteristics between two walking conditions, wearing and not wearing a portable gas analysis system, and assess the relationship between stance time variability and energy cost of walking in older adults. Subjects: Forty older adults with preferred walking speeds between 0.8-1.0 m/s were selected. Methods: Gait characteristics (gait speed, step length, step width, step time, stance time, single-support time, double-support time, step length variability, step width variability, and stance time variability) were recorded (variability derived as standard deviation of all steps) while participants completed eight passes over a computerized walkway, with and without wearing the portable device. Next, concurrent measures of stance time variability and oxygen consumption were collected during four walking conditions (Overground, Rollator, Treadmill, Treadmill Slow), additional measures were recorded as potential confounders (gait speed, biomechanics, fear of falling, confidence in walking, co-morbidities) or to describe sample (age, race, gender). Analyses: Paired t-tests were used to assess differences between gait characteristics with and without a portable device. ICC’s were calculated to describe the agreement between measures. Bivariate analyses were performed to determine association between stance time variability and energy cost of walking during overground walking. Regression was used to assess for independent contributors to energy cost; confounders simultaneously entered first, followed by stance time variability. Additional bivariate analyses were performed for additional conditions. Individual regressions were performed to assess for independent contributors to cost; confounders simultaneously entered first, followed by stance time variability. Mixed-effects models were used to compare stance time variability and energy cost between walking conditions. Post-hoc analysis used to estimate differences between paired conditions of interest. Results and Clinical Relevance: Our study showed no evidence suggesting wearing a portable device alters overground gait characteristics. Our study also indicates no direct association between stance time variability and energy cost of walking, across any walking conditions. Stance time variability was lower on the treadmill, however, no subsequent changes were observed in energy cost. Continued efforts are needed to investigate multiple contributors to energy cost and assess the unique interactions, modifying, and mediating influences these variables have on energy cost of walking

Methodological Considerations for Amish-Focused Opinion Research: Lessons from a Study of Beliefs and Practices about Agriculture and the Environment

Certain aspects of Amish agriculture have been studied extensively but much is still unknown about Amish environmental attitudes and beliefs. This is due, in part, to the difficulty of directly soliciting responses from adherents. This article—part of a larger study of the Kishacoquillas Valley Amish settlement in Mifflin County, Pennsylvania—reflects on methodological challenges that arose during a study on Amish environmental attitudes and behaviors. Farmers from two Amish groups, as well as two non-Amish groups used for comparison, were interviewed about their environmental attitudes. Recruiting Amish participants for interviews was difficult due to the limited use of modern telecommunications technology, what can be perceived as a general suspicion of non-members, and concerns about possible publicity. Further, the use of standard academic research method protocols and survey instruments proved challenging with the Amish. Administering an academic-level survey to the Amish, a group whose formal schooling generally ends at eighth grade and whose first language is Pennsylvania Dutch, posed challenges for the interviewees’ understanding of certain technical terms and for the interviewer’s interpretation of responses. As the study unfolded, methodological flexibility was necessary to adapt the research to the people. Namely, open-ended questions were added to the formal survey in order to learn more about Amish attitudes about stewardship. These study reflections suggest that researchers should take time to learn about the local context and culture and be flexible in selecting and adapting methodological instruments. [Abstract by author.

Using non-human primates to benefit humans: research and organ transplantation

Emerging biotechnology may soon allow the creation of genetically human organs inside animals, with non-human primates (henceforth simply "primates”) and pigs being the best candidate species. This prospect raises the question of whether creating organs in primates in order to then transplant them into humans would be more (or less) acceptable than using them for research. In this paper, we examine the validity of the purported moral distinction between primates and other animals, and analyze the ethical acceptability of using primates to create organs for human use

Amphiregulin cooperates with bone morphogenetic protein 15 to increase oocyte developmental competence by gap junction-mediated enhanced metabolite supply

This study assessed the participation of amphiregulin (AREG) and bone morphogenetic protein 15 (BMP15) during maturation of bovine cumulus oocyte complexes (COCs) on cumulus cell function and their impact on subsequent embryo development. AREG treatment of COCs enhanced blastocyst formation and quality only when in the presence of BMP15. Expression of hyaluronan synthase 2 was enhanced by follicle stimulating hormone (FSH) but not by AREG, which was reflected in the level of cumulus expansion. Although both FSH and AREG stimulated glycolysis, AREG treated COCs had higher glucose consumption, lactate production and ratio of lactate production to glucose uptake. Autofluorescence levels in oocytes, indicative of NAD(P)H and FAD++, were increased with combined AREG and BMP15 treatment of COCs. In contrast, these treatments did not alter autoflouresence levels when cumulus cells were removed from oocytes, even in the presence of other COCs, suggesting oocyte-cumulus gap-junctional communication (GJC) is required. FSH contributed to maintaining GJC for an extended period of time. Remarkably, BMP15 was equally effective at maintaining GJC even in the presence of AREG. Hence, AREG stimulation of COC glycolysis and BMP15 preservation of GJC may facilitate efficient transfer of metabolites from cumulus cells to the oocyte thereby enhancing oocyte developmental competence. These results have implications for improving in vitro oocyte maturation systems.Satoshi Sugimura, Lesley J Ritter, Melanie L Sutton-McDowall, David G Mottershead, Jeremy G Thompson and Robert B Gilchris

Current issues in medically assisted reproduction and genetics in Europe: research, clinical practice, ethics, legal issues and policy. European Society of Human Genetics and European Society of Human Reproduction and Embryology.

In March 2005, a group of experts from the European Society of Human Genetics and European Society of Human Reproduction and Embryology met to discuss the interface between genetics and assisted reproductive technology (ART), and published an extended background paper, recommendations and two Editorials. Seven years later, in March 2012, a follow-up interdisciplinary workshop was held, involving representatives of both professional societies, including experts from the European Union Eurogentest2 Coordination Action Project. The main goal of this meeting was to discuss developments at the interface between clinical genetics and ARTs. As more genetic causes of reproductive failure are now recognised and an increasing number of patients undergo testing of their genome before conception, either in regular health care or in the context of direct-to-consumer testing, the need for genetic counselling and preimplantation genetic diagnosis (PGD) may increase. Preimplantation genetic screening (PGS) thus far does not have evidence from randomised clinical trials to substantiate that the technique is both effective and efficient. Whole-genome sequencing may create greater challenges both in the technological and interpretational domains, and requires further reflection about the ethics of genetic testing in ART and PGD/PGS. Diagnostic laboratories should be reporting their results according to internationally accepted accreditation standards (International Standards Organisation - ISO 15189). Further studies are needed in order to address issues related to the impact of ART on epigenetic reprogramming of the early embryo. The legal landscape regarding assisted reproduction is evolving but still remains very heterogeneous and often contradictory. The lack of legal harmonisation and uneven access to infertility treatment and PGD/PGS fosters considerable cross-border reproductive care in Europe and beyond. The aim of this paper is to complement previous publications and provide an update of selected topics that have evolved since 2005

Geographic Variability in Elevation and Topographic Constraints on the Distribution of Native and Nonnative Trout in the Great Basin

Understanding local and geographic factors influencing species distributions is a prerequisite for conservation planning. Our objective in this study was to model local and geographic variability in elevations occupied by native and nonnative trout in the northwestern Great Basin, USA. To this end, we analyzed a large existing data set of trout presence (5,156 observations) to evaluate two fundamental factors influencing occupied elevations: climate-related gradients in geography and local constraints imposed by topography. We applied quantile regression to model upstream and downstream distribution elevation limits for each trout species commonly found in the region (two native and two nonnative species). With these models in hand, we simulated an upstream shift in elevation limits of trout distributions to evaluate potential consequences of habitat loss. Downstream elevation limits were inversely associated with latitude, reflecting regional gradients in temperature. Upstream limits were positively related to maximum stream elevation as expected. Downstream elevation limits were constrained topographically by valley bottom elevations in northern streams but not in southern streams, where limits began well above valley bottoms. Elevation limits were similar among species. Upstream shifts in elevation limits for trout would lead to more habitat loss in the north than in the south, a result attributable to differences in topography. Because downstream distributions of trout in the north extend into valley bottoms with reduced topographic relief, trout in more northerly latitudes are more likely to experience habitat loss associated with an upstream shift in lower elevation limits. By applying quantile regression to relatively simple information (species presence, elevation, geography, topography), we were able to identify elevation limits for trout in the Great Basin and explore the effects of potential shifts in these limits that could occur in response to changing climate conditions that alter streams directly (e.g., through changes in temperature and precipitation) or indirectly (e.g., through changing water use)

Sox2 Is Required for Maintenance and Differentiation of Bronchiolar Clara, Ciliated, and Goblet Cells

The bronchioles of the murine lung are lined by a simple columnar epithelium composed of ciliated, Clara, and goblet cells that together mediate barrier function, mucociliary clearance and innate host defense, vital for pulmonary homeostasis. In the present work, we demonstrate that expression of Sox2 in Clara cells is required for the differentiation of ciliated, Clara, and goblet cells that line the bronchioles of the postnatal lung. The gene was selectively deleted in Clara cells utilizing Scgb1a1-Cre, causing the progressive loss of Sox2 in the bronchioles during perinatal and postnatal development. The rate of bronchiolar cell proliferation was decreased and associated with the formation of an undifferentiated, cuboidal-squamous epithelium lacking the expression of markers of Clara cells (Scgb1a1), ciliated cells (FoxJ1 and α-tubulin), and goblet cells (Spdef and Muc5AC). By adulthood, bronchiolar cell numbers were decreased and Sox2 was absent in extensive regions of the bronchiolar epithelium, at which time residual Sox2 expression was primarily restricted to selective niches of CGRP staining neuroepithelial cells. Allergen-induced goblet cell differentiation and mucus production was absent in the respiratory epithelium lacking Sox2. In vitro, Sox2 activated promoter-luciferase reporter constructs for differentiation markers characteristic of Clara, ciliated, and goblet cells, Scgb1a1, FoxJ1, and Agr2, respectively. Sox2 physically interacted with Smad3 and inhibited TGF-β1/Smad3-mediated transcriptional activity in vitro, a pathway that negatively regulates proliferation. Sox2 is required for proliferation and differentiation of Clara cells that serve as the progenitor cells from which Clara, ciliated, and goblet cells are derived

The paradox of cooling streams in a warming world:Regional climate trends do not parallel variable local trends in stream temperature in the Pacific continental United States

Temperature is a fundamentally important driver of ecosystem processes in streams. Recent warming of terrestrial climates around the globe has motivated concern about consequent increases in stream temperature. More specifically, observed trends of increasing air temperature and declining stream flow are widely believed to result in corresponding increases in stream temperature. Here, we examined the evidence for this using long-term stream temperature data from minimally and highly human-impacted sites located across the Pacific continental United States. Based on hypothesized climate impacts, we predicted that we should find warming trends in the maximum, mean and minimum temperatures, as well as increasing variability over time. These predictions were not fully realized. Warming trends were most prevalent in a small subset of locations with longer time series beginning in the 1950s. More recent series of observations (1987-2009) exhibited fewer warming trends and more cooling trends in both minimally and highly human-influenced systems. Trends in variability were much less evident, regardless of the length of time series. Based on these findings, we conclude that our perspective of climate impacts on stream temperatures is clouded considerably by a lack of long-term data on minimally impacted streams, and biased spatio-temporal representation of existing time series. Overall our results highlight the need to develop more mechanistic, process-based understanding of linkages between climate change, other human impacts and stream temperature, and to deploy sensor networks that will provide better information on trends in stream temperatures in the future. Citation: Arismendi, I., S. L. Johnson, J. B. Dunham, R. Haggerty, and D. Hockman-Wert (2012), The paradox of cooling streams in a warming world: Regional climate trends do not parallel variable local trends in stream temperature in the Pacific continental United States, Geophys. Res. Lett., 39, L10401, doi:10.1029/2012GL051448.Keywords: River temperature, Wildfire tests, Western, Snowpac