Search

Although compartmentalization of the eye seems to promote its experimental manipulation, drug penetration to its posterior part is severely limited by hard barriers thus hindering drug development for eye diseases. In particular, angiogenesis-related retinal diseases share common mechanisms and are responsible for the majority of cases of blindness. Their prevalence is globally increasing mostly because of the increased incidence of systemic pathologies in the adult. Despite the number of preclinical findings demonstrating the efficacy of novel treatments, therapy of retinal neovascular diseases still remains confined to intravitreal anti-vascular endothelial growth factor treatments with some extension to anti-inflammatory therapy. In the mare magnum of preclinical findings aimed to develop novel avenues for future therapies, most compounds, despite their efficacy in experimental models, do not seem to meet the criteria for their therapeutic application. In particular, the groove between preclinical findings and their clinical application increases instead of decreasing and the attempt to bridging the gap between them creates intense frustration and a sense of defeat. In this complex scenario, we will discuss here the role that overactivation of the sympathetic system plays in retinal vessel proliferation in response to hypoxia using the oxygen-induced retinopathy (OIR) model. The potential application of the beta-adrenoceptor (ß-AR) blockade with propranolol to the treatment of retinopathy of prematurity will be also discussed in light of preclinical findings in the OIR model and clinical trials using propranolol in preterm infants either per os or as eye drops. [ABSTRACT FROM AUTHOR]

Although compartmentalization of the eye seems to promote its experimental manipulation, drug penetration to its posterior part is severely limited by hard barriers thus hindering drug development for eye diseases. In particular, angiogenesis-related retinal diseases share common mechanisms and are responsible for the majority of cases of blindness. Their prevalence is globally increasing mostly because of the increased incidence of systemic pathologies in the adult. Despite the number of preclinical findings demonstrating the efficacy of novel treatments, therapy of retinal neovascular diseases still remains confined to intravitreal anti-vascular endothelial growth factor treatments with some extension to anti-inflammatory therapy. In the mare magnum of preclinical findings aimed to develop novel avenues for future therapies, most compounds, despite their efficacy in experimental models, do not seem to meet the criteria for their therapeutic application. In particular, the groove between preclinical findings and their clinical application increases instead of decreasing and the attempt to bridging the gap between them creates intense frustration and a sense of defeat. In this complex scenario, we will discuss here the role that overactivation of the sympathetic system plays in retinal vessel proliferation in response to hypoxia using the oxygen-induced retinopathy (OIR) model. The potential application of the beta-adrenoceptor (β-AR) blockade with propranolol to the treatment of retinopathy of prematurity will be also discussed in light of preclinical findings in the OIR model and clinical trials using propranolol in preterm infants either per os or as eye drops.

The issue of vertical capacity expansion of municipal solid waste (MSW) landfills with reinforced soil walls (RSWs) is addressed in the present investigation. The influence of different conditions of leachate levels in MSW landfills is a major cause of translational failures. Poor hydraulic conductivity, clogging of drainage because of fines, and freezing of drainage in landfills are the crucial factors of the buildup of leachate pressure. Heterogeneity and different fill ages in MSW landfills gradually change the inherent properties of landfills. The assumption-independent component failures of sliding, eccentricity, bearing capacity, tension, and pullout modes in predicting the series system reliability index of RSWs against translational failure under six leachate level conditions may produce large errors because component failures are usually dependent on one another. Therefore, the present paper demonstrates the feasibility of considering dependent failure modes to estimate the dimensions of RSWs to maintain the external and internal stability under six different leachate buildup conditions. The variability associated with the cohesion of solid waste, the apparent cohesion between liner components beneath the wedges, the friction angle of MSW, and the interface friction angle beneath the wedges is considered for the estimation of the lower bound of the series system reliability index. The limit equilibrium method is employed to assess the stability of an RSW for an expanded MSW landfill. Further, the design charts for the optimum values of width and height of the RSW are provided for different leachate levels (hw) under six leachate buildup conditions by targeting various lower bounds of a system reliability index ≥3.0. The design values of the number of reinforcement layers (n) are also provided corresponding to the optimum dimensions of the RSW subjected to different leachate levels. [ABSTRACT FROM AUTHOR]

Despite achieving remarkable success in understanding the cellular, molecular and pathophysiological aspects of stroke, translation from preclinical research has always remained an area of debate. Although thousands of experimental compounds have been reported to be neuro-protective, their failures in clinical setting have left the researchers and stakeholders in doldrums. Though the failures described have been excruciating, they also give us a chance to refocus on the shortcomings. For better translational value, evidences from preclinical studies should be robust and reliable. Preclinical study design has a plethora of variables affecting the study outcome. Hence, this review focusses on the factors to be considered for a well-planned preclinical study while adhering to guidelines with emphasis on the study design, commonly used animal models, their limitations with special attention on various preventable attritions including comorbidities, aged animals, time of dosing, outcome measures and physiological variables along with the concept of multicentric preclinical randomized controlled trials. Here, we provide an overview of a panorama of practical aspects, which could be implemented, so that a well-defined preclinical study would result in a neuro-protectant with better translational value. [ABSTRACT FROM AUTHOR]

Background: Neurological and ophthalmological neurodegenerative diseases in large part share underlying biology and pathophysiology. Despite extensive preclinical research on neuroprotection that in many cases bridges and unifies both fields, only a handful of neuroprotective therapies have succeeded clinically in either. Main body: Understanding the commonalities among brain and neuroretinal neurodegenerations can help develop innovative ways to improve translational success in neuroprotection research and emerging therapies. To do this, analysis of why translational research in neuroprotection fails necessitates addressing roadblocks at basic research and clinical trial levels. These include optimizing translational approaches with respect to biomarkers, therapeutic targets, treatments, animal models, and regulatory pathways. Conclusion: The common features of neurological and ophthalmological neurodegenerations are useful for outlining a path forward that should increase the likelihood of translational success in neuroprotective therapies. [ABSTRACT FROM AUTHOR]

BackgroundNeurological and ophthalmological neurodegenerative diseases in large part share underlying biology and pathophysiology. Despite extensive preclinical research on neuroprotection that in many cases bridges and unifies both fields, only a handful of neuroprotective therapies have succeeded clinically in either.Main bodyUnderstanding the commonalities among brain and neuroretinal neurodegenerations can help develop innovative ways to improve translational success in neuroprotection research and emerging therapies. To do this, analysis of why translational research in neuroprotection fails necessitates addressing roadblocks at basic research and clinical trial levels. These include optimizing translational approaches with respect to biomarkers, therapeutic targets, treatments, animal models, and regulatory pathways.ConclusionThe common features of neurological and ophthalmological neurodegenerations are useful for outlining a path forward that should increase the likelihood of translational success in neuroprotective therapies.

Slope failures can endanger human life and cause infrastructural destruction and socioeconomic loss. Geoscientists have strived to develop constitutive models and real-time slope monitoring models and systems to abate these processes. Most research studies have proposed models which describe the dynamics of wedge-shaped soil masses which do not mimic real field conditions. In this study, failure dynamics of spherical-cap-shaped soil masses on an inclined slope section undergoing purely translational displacement are described using empirical models derived from inertial forces in action for varying hydrological conditions. Validation of model results was done through experimental tests carried out on a laboratory flume. Empirical models representing rainfall intensity, soil water content, pore-water pressure, factor of safety, and displacement were derived. More pertinently, the empirical model for the factor of safety is derived considering the moist unit weight of the soil as opposed to earlier models which focused on saturated conditions only. Model and experimental results indicate close concurrence, especially for the factor of safety with root mean square error of 0.0385 and r2 of 0.6381. Since the models are physics based, they can be applied on a variety of rainfall-induced shallow landslides on relatively steep slopes.

Introduction: Preclinical studies provide foundational knowledge to develop new effective treatments for use in clinical practice. Similar to clinical exercise oncology studies, it is also important to monitor, identify and/or avoid cancer-induced complications in preclinical (e.g., murine) exercise oncology studies. This may help close the gap between preclinical and clinical exercise oncology studies. The aim of the present mini review is to provide insight into exercise protocol design in preclinical exercise oncology studies in order to close the preclinical-clinical gap. A secondary aim was to examine exercise-responsive outcomes in the preclinical versus clinical setting. Method: We reviewed animal studies in exercise oncology. A literature search was performed in PubMed/Medline and studies in English were screened. Results: We found that the majority of preclinical exercise protocols have not been at least tested clinically. We found some evidence that certain outcomes of preclinical studies (e.g., markers of cellular and molecular adaptation) that translate to clinical studies. However, this translation was dependent on the use, by investigators in their study design, of suitable and applicable preclinical exercise protocols. Conclusions: Cancer and its treatment-induced complications (e.g., fatigue, cardiac atrophy, cachexia, etc.) have largely been ignored in the exercise protocols of preclinical oncology studies. Preclinical exercise oncology studies should consider the limitations of human exercise oncology studies when conducting gap analysis for their study design to increase the probability that findings related to mechanistic adaptations in exercise oncology will be translatable to the clinical setting. By virtue of paying heed to patient compliance and adverse effects, clinical exercise oncology research teams must design relevant, feasible exercise protocols; researchers in preclinical exercise oncology should also take such factors into consideration in order to help bridge the gap between preclinical and clinical studies in exercise oncology.

The pharmaceutical industry has long known that ∼80% of the results of academic laboratories cannot be reproduced when repeated in industry laboratories. Yet academic investigators are typically unaware of this problem, which severely impedes the drug development process. This academic–industrial complication is not one of deception, but rather a complex issue related to how scientific research is carried out and translated in strikingly different enterprises. This Opinion describes the reasons for inconsistencies between academic and industrial laboratories and what can be done to repair this failure of translation. [ABSTRACT FROM AUTHOR]

Aims Numerous anti-inflammatory drugs have been tested in large animal studies of myocardial infarction (MI). Despite positive results, translation of anti-inflammatory strategies into clinical practice has proved to be difficult. Critical disparities between preclinical and clinical study design that influence efficacy may partly be responsible for this translational failure. The aim of the present systematic review was to better understand which factors underlie the failure of transition towards the clinic. Methods and results Meta-analysis and regression of large animal studies were performed to identify sources that influenced effect size of anti-inflammatory compounds in large animal models of MI. We included 183 studies, containing 3331 large animals. Infarct size (IS) as a ratio of the area at risk (12.7%; 95% confidence interval, CI 11.1-14.4%, P, 0.001) and IS as a ratio of the left ventricle (3.9%; 95% CI 3.1-4.7%, P, 0.001) were reduced in treatment compared with control groups. Effect size was higher when outcome was assessed early after MI (P = 0.013) and where studies included only male animals (P < 0.001). Mortality in treated animals was higher in studies that blinded the investigator during the experiment (P = 0.041) and depended on the type of drug used (P < 0.001). Conclusions As expected, treatment with anti-inflammatory drugs leads to smaller infarct size in large animal MI models. Timing of outcome assessment, sex, and study quality are significantly associated with outcome and may explain part of the translational failure in clinical settings. Effect size depends on the type of drug used, enabling identification of compounds for future clinical testing. [ABSTRACT FROM AUTHOR]

This paper extends a previously developed three-part wedge method for the seismic stability analysis of the landfill with a triangular berm using pseudo-static method, and moreover, the translation failure condition of the landfill along under bottom of the berm is only presented. In the seismic impact zone, it is necessary to consider the impact of the seismic force on the stability of the landfill. Generally, apart from the horizontal seismic force, the landfill is also subjected to both upward and downward vertical seismic forces. The downward vertical seismic force has a positive impact on the seismic stability of the landfill, while the upward vertical seismic force is just opposite. Therefore, simply ignoring vertical seismic force, the seismic stability of the landfill will be overestimated or underestimated in the seismic condition. Besides, the seismic yield coefficient is calculated by assuming FS = 2FS and the ratio of vertical seismic coefficient to horizontal seismic coefficient is equal to 2/3. [ABSTRACT FROM AUTHOR]

This paper extends a previously developed method of the writers by using a pseudostatic approach to conduct seismic stability analysis for potential translational failures of multilayer lined landfills. Assuming that the designed seismic coefficient, ks, is known, the factor of safety against translational failure for lined landfills can be calculated from the new developed equations. The critical interface with the seismic yield coefficient, ky, is generally located at different interfaces along the back slope and along the base. The failure surface is seen to transfer from one interface to another with changes of dimensions of the top width, depth, and front slope of the waste mass. Using this method, a waste filling sequence can be generated so as to maintain the ky-value above a stipulated value during landfill operations. It is important to ensure that the minimum ky-value at the critical interface is always equal to or greater than a targeted value during the waste filling sequence and after closure corresponding to the different geometric dimensions of the waste mass. [ABSTRACT FROM AUTHOR]

This paper aims to assess the effect of nonlinearity of the soil shear strength envelope on the sliding mass configurations and the minimum two- and three-dimensional factors of safety for slopes susceptible to translational failure in both static and seismic conditions. An extensive parametric study was conducted using slope models and nonlinear soil strength envelopes that simulate translational failure case histories. Analysis of the results led to the development of stability charts that do not require an iterative procedure when determining the factors of safety. The introduction of a two-dimensional stability number and three-dimensional stability function, the values of which depend on the degrees of nonlinearity of the involved soils’ strength envelopes, has made it possible to develop such charts. These charts give the practicing geotechnical engineer a reliable and fast method to analyze translational failures. Using available software in such an analysis can be complicated if shear resistance along the sliding mass vertical sides and nonlinearity of soil shear strength envelopes are considered. Numerical examples and a case history are given to verify the reliability and illustrate the different applications of these charts. Cet article évalue l’effet de la non linéarité de l’enveloppe de résistance au cisaillement du sol sur les configurations des masses glissantes, ainsi que les facteurs de sécurité minimaux en deux et trois dimensions pour des pentes susceptibles de rupture en translation en conditions autant statiques que sismiques. Une vaste étude paramétrique a été effectuée avec des modèles de pentes et des enveloppes de résistance non linéaires qui simulent des cas historiques de rupture en translation. L’analyse des résultats a permis de développer des chartes de stabilité qui ne nécessitent pas une procédure itérative pour déterminer les facteurs de sécurité. Le développement de ces chartes a été possible grâce à l’introduction du nombre de stabilité en deux dimensions et de la fonction de stabilité en trois dimensions, dont les valeurs dépendent du degré de non linéarité des enveloppes de résistance des sols impliqués. Les chartes offrent aux praticiens une méthode rapide et fiable pour l’analyse des ruptures en translation. L’utilisation des logiciels disponibles pour une telle analyse peut être compliquée si l’on considère la résistance au cisaillement le long des bords verticaux de la masse glissante et la non linéarité des enveloppes de résistance au cisaillement des sols. Des exemples numériques et une historique de cas sont présentés afin de vérifier la fiabilité des chartes ainsi que pour illustrer les différentes applications de ces chartes. [ABSTRACT FROM AUTHOR]

Abstract: The aim of this study is to develop a computer program (FRACEK) for fractal dimensions of amorphous areas, and to apply this program on various mass movements. FRACEK has been developed using Java technology with an object-oriented approach. The input of FRACEK is a set of 2-dimensional images including the amorphous areas of which fractal values are to be computed. FRACEK is a user-friendly program that can be used to calculate fractal dimensions easily and can be used in various earth science applications. In this study, published maps were utilized when applying FRACEK to various mass movements. A total of 116 mass movement data were employed. In addition to the fractal dimensions (D), the width (W) to length (L) ratio of each mass movement was calculated. The relationship between the W/L ratio and the D was investigated. Relatively high correlations were found between the D and the W/L ratio. The results of this study indicate that it is possible to make a differentiation among the mass movements using the fractal dimension. However, further research is required for evaluation all types of mass movements. [Copyright &y& Elsevier]

A translational failure of a highway embankment constructed on sloping ground may occur either in the mode of overall instability or in the mode of local instability. The stability analysis of the first mode is based on the assumption that the whole cross-section of the embankment will slide along the inclined base surface, whilst the second mode is based on the assumption of Rankine's active state of stress. In this paper the determination of the prevalent mode of failure - overall or local - is provided via a chart derived from force polygon analysis, with the dimensionless parameter, c'/γH, and the effective friction angle, φ', as its axes. Furthermore, the determination of the most probable failure plane in the cross-section of the embankment is attempted and additionally the role of the cohesion in the stability is discussed. Finally, an estimation of the amplitude of failure at the road surface in the case of local instability is given. A confirmation of the aforementioned was achieved through case studies of highway embankments that have failed as a consequence of water infiltration and the development of high pore water pressures. A comparison between the local and the respective overall instability safety factor is given. [ABSTRACT FROM AUTHOR]

Copyright of Canadian Geotechnical Journal is the property of Canadian Science Publishing and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)

Simple Summary: Noncommunicable diseases, such as Alzheimer's disease, and breast and prostate cancer, are becoming increasingly prevalent in Western countries. To better elucidate the onset and evolution of these pathologies and ultimately design new preventive and therapeutic strategies, research activities focused on these biomedical areas have been supported by the European Union for more than two decades. While research has globally contributed to increase our understanding of the pathological mechanisms underlying these diseases, the failure rate in drug development still remains very high. Nowadays, it is important to monitor the contribution to innovation and impact of funded research by means of defined indicators. Dementia and cancer are becoming increasingly prevalent in Western countries. In the last two decades, research focused on Alzheimer's disease (AD) and cancer, in particular, breast cancer (BC) and prostate cancer (PC), has been substantially funded both in Europe and worldwide. While scientific research outcomes have contributed to increase our understanding of the disease etiopathology, still the prevalence of these chronic degenerative conditions remains very high across the globe. By definition, no model is perfect. In particular, animal models of AD, BC, and PC have been and still are traditionally used in basic/fundamental, translational, and preclinical research to study human disease mechanisms, identify new therapeutic targets, and develop new drugs. However, animals do not adequately model some essential features of human disease; therefore, they are often unable to pave the way to the development of drugs effective in human patients. The rise of new technological tools and models in life science, and the increasing need for multidisciplinary approaches have encouraged many interdisciplinary research initiatives. With considerable funds being invested in biomedical research, it is becoming pivotal to define and apply indicators to monitor the contribution to innovation and impact of funded research. Here, we discuss some of the issues underlying translational failure in AD, BC, and PC research, and describe how indicators could be applied to retrospectively measure outputs and impact of funded biomedical research. [ABSTRACT FROM AUTHOR]