Translational Failure Research Articles

Pragmatic failures in public-sign translation: an eco-pragma-translatology analysis of environmental signage in Quanzhou

Abstract This study proposes an integrated model called the Eco-Pragma-Translatology Model (EPTM) with four Kernel Guidelines for accounting for translation of public (environmental protection) signs. An EPTM analysis of pragmatic failures in public environmental protection signs (from the database) demonstrates that the ubiquitous errors and mistakes of rendering come under the rubric of pragmalinguistic failures of translation, sociopragmatic failures, or pragmatic failures straddling boundaries and leads to the conclusion that translators should correspondingly enhance their pragmalinguistic and/or sociopragmatic competence. EPTM is a new, interdisciplinary theoretical approach that largely applies to issues of poor translation of public signs.

Natural and synthetic antioxidants targeting cardiac oxidative stress and redox signaling in cardiometabolic diseases

Cardiometabolic diseases (CMDs) are metabolic diseases (e.g., obesity, diabetes, atherosclerosis, rare genetic metabolic diseases, etc.) associated with cardiac pathologies. Pathophysiology of most CMDs involves increased production of reactive oxygen species and impaired antioxidant defense systems, resulting in cardiac oxidative stress (OxS). To alleviate OxS, various antioxidants have been investigated in several diseases with conflicting results. Here we review the effect of CMDs on cardiac redox homeostasis, the role of OxS in cardiac pathologies, as well as experimental and clinical data on the therapeutic potential of natural antioxidants (including resveratrol, quercetin, curcumin, vitamins A, C, and E, coenzyme Q10, etc.), synthetic antioxidants (including N-acetylcysteine, SOD mimetics, mitoTEMPO, SkQ1, etc.), and promoters of antioxidant enzymes in CMDs. As no antioxidant indicated for the prevention and/or treatment of CMDs has reached the market despite the large number of preclinical and clinical studies, a sizeable translational gap is evident in this field. Thus, we also highlight potential underlying factors that may contribute to the failure of translation of antioxidant therapies in CMDs.

Neuroprotective effect of hypoxic preconditioning and neuronal activation in a in vitro human model of the ischemic penumbra

Objective. In ischemic stroke, treatments to protect neurons from irreversible damage are urgently needed. Studies in animal models have shown that neuroprotective treatments targeting neuronal silencing improve brain recovery, but in clinical trials none of these were effective in patients. This failure of translation poses doubts on the real efficacy of treatments tested and on the validity of animal models for human stroke. Here, we established a human neuronal model of the ischemic penumbra by using human induced pluripotent stem cells and we provided an in-depth characterization of neuronal responses to hypoxia and treatment strategies at the network level.Approach. We generated neurons from induced pluripotent stem cells derived from healthy donor and we cultured them on micro-electrode arrays. We measured the electrophysiological activity of human neuronal networks under controlled hypoxic conditions. We tested the effect of different treatment strategies on neuronal network functionality.Main results. Human neuronal networks are vulnerable to hypoxia reflected by a decrease in activity and synchronicity under low oxygen conditions. We observe that full, partial or absent recovery depend on the timing of re-oxygenation and we provide a critical time threshold that, if crossed, is associated with irreversible impairments. We found that hypoxic preconditioning improves resistance to a second hypoxic insult. Finally, in contrast to previously tested, ineffective treatments, we show that stimulatory treatments counteracting neuronal silencing during hypoxia, such as optogenetic stimulation, are neuroprotective.Significance. We presented a human neuronal model of the ischemic penumbra and we provided insights that may offer the basis for novel therapeutic approaches for patients after stroke. The use of human neurons might improve drug discovery and translation of findings to patients and might open new perspectives for personalized investigations.

Neuropharmacology in traumatic brain injury: from preclinical to clinical neuroprotection?

Traumatic brain injury (TBI) constitutes a major health problem worldwide and is a leading cause of death and disability in individuals, contributing to devastating socioeconomic consequences. Despite numerous promising pharmacological strategies reported as neuroprotective in preclinical studies, the translation to clinical trials always failed, albeit the great diversity of therapeutic targets evaluated. In this review, first, we described epidemiologic features, causes, and primary and secondary injuries of TBI. Second, we outlined the current literature on animal models of TBI, and we described their goals, their advantages and disadvantages according to the species used, the type of injury induced, and their clinical relevance. Third, we defined the concept of neuroprotection and discussed its evolution. We also identified the reasons that might explain the failure of clinical translation. Then, we reviewed post‐TBI neuroprotective treatments with a focus on the following pleiotropic drugs, considered “low hanging fruit” with high probability of success: glitazones, glibenclamide, statins, erythropoietin, and progesterone, that were largely tested and demonstrated efficient in preclinical models of TBI. Finally, our review stresses the need to establish a close cooperation between basic researchers and clinicians to ensure the best clinical translation for neuroprotective strategies for TBI.

Benefits and obstacles to cell therapy in neonates: The INCuBAToR (Innovative Neonatal Cellular Therapy for Bronchopulmonary Dysplasia: Accelerating Translation of Research).

Cell‐based therapies hold promise to substantially curb complications from extreme preterm birth, the main cause of death in children below the age of 5 years. Exciting preclinical studies in experimental neonatal lung injury have provided the impetus for the initiation of early phase clinical trials in extreme preterm infants at risk of developing bronchopulmonary dysplasia. Clinical translation of promising therapies, however, is slow and often fails. In the adult population, results of clinical trials so far have not matched the enticing preclinical data. The neonatal field has experienced many hard‐earned lessons with the implementation of oxygen therapy or postnatal steroids. Here we briefly summarize the preclinical data that have permitted the initiation of early phase clinical trials of cell‐based therapies in extreme preterm infants and describe the INCuBAToR concept (Innovative Neonatal Cellular Therapy for Bronchopulmonary Dysplasia: Accelerating Translation of Research), an evidence‐based approach to mitigate the risk of translating advanced therapies into this vulnerable patient population. The INCuBAToR addresses several of the shortcomings at the preclinical and the clinical stage that usually contribute to the failure of clinical translation through (a) systematic reviews of preclinical and clinical studies, (b) integrated knowledge transfer through engaging important stakeholders early on, (c) early economic evaluation to determine if a novel therapy is viable, and (d) retrospective and prospective studies to define and test ideal eligibility criteria to optimize clinical trial design. The INCuBAToR concept can be applied to any novel therapy in order to enhance the likelihood of success of clinical translation in a timely, transparent, rigorous, and evidence‐based fashion.

The Hydromechanical Interplay in the Simplified Three-Dimensional Limit Equilibrium Analyses of Unsaturated Slope Stability

This paper presents a three-dimensional slope stability limit equilibrium solution for translational planar failure modes. The proposed solution uses Bishop’s average skeleton stress combined with the Mohr–Coulomb failure criterion to describe soil strength evolution under unsaturated conditions while its formulation ensures a natural and smooth transition from the unsaturated to the saturated regime and vice versa. The proposed analytical solution is evaluated by comparing its predictions with the results of the Ruedlingen slope failure experiment. The comparison suggests that, despite its relative simplicity, the analytical solution can capture the experimentally observed behaviour well and highlights the importance of considering lateral resistance together with a realistic interplay between mechanical parameters (cohesion) and hydraulic (pore water pressure) conditions.

Preclinical Neuropathic Pain Assessment; the Importance of Translatability and Bidirectional Research.

For patients suffering with chronic neuropathic pain the need for suitable novel therapies is imperative. Over recent years a contributing factor for the lack of development of new analgesics for neuropathic pain has been the mismatch of primary neuropathic pain assessment endpoints in preclinical vs. clinical trials. Despite continuous forward translation failures across diverse mechanisms, reflexive quantitative sensory testing remains the primary assessment endpoint for neuropathic pain and analgesia in animals. Restricting preclinical evaluation of pain and analgesia to exclusively reflexive outcomes is over simplified and can be argued not clinically relevant due to the continued lack of forward translation and failures in the clinic. The key to developing new analgesic treatments for neuropathic pain therefore lies in the development of clinically relevant endpoints that can translate preclinical animal results to human clinical trials. In this review we discuss this mismatch of primary neuropathic pain assessment endpoints, together with clinical and preclinical evidence that supports how bidirectional research is helping to validate new clinically relevant neuropathic pain assessment endpoints. Ethological behavioral endpoints such as burrowing and facial grimacing and objective measures such as electroencephalography provide improved translatability potential together with currently used quantitative sensory testing endpoints. By tailoring objective and subjective measures of neuropathic pain the translatability of new medicines for patients suffering with neuropathic pain will hopefully be improved.

A failure of forward translation? The case of neuroprotection

Vessel Plus is an open acccess journal, which publishes articles related to vascular diseases, including acute respiratory distress syndrome, aneurysm, atherosclerosis, hypertension, stroke, peripheral vascular or pulmonary vascular diseases, etc.

Clinical Translation of Cell Therapies in Stroke (CT2S) Checklist\u2014a pragmatic tool to accelerate development of cell therapy products

BackgroundCell therapies present an exciting potential but there is a long history of expensive translational failures in stroke research. Researchers engaged in cell therapy research would benefit from a practical framework that can help in planning research and development of investigational cell therapies into viable medical products.MethodsWe developed a checklist using a mixed methodology approach to evaluate the impact of study design, regulatory policy, ethical, and health economic considerations for efficient implementation of early phase cell therapy studies.ResultsThe checklist comprises a series of questions arranged under four domains: the first concerns study design such as characterization of target study population, trial design, endpoints and operational fit of dosage, time, and route of administration to target populations. A second domain addresses the data package required for regulatory approval relevant to the intended use (allogeneic/autologous; homologous/non-homologous; nature of cell processing). The third domain comprises patient involvement to ensure relevant data is collected via targeted study design. The final domain requires the team to determine the critical data elements that could be built into study design to enable health economic data collection to be started at an early phase of the study.ConclusionsThe CT2S checklist can help to determine areas of expertise gaps and enable research groups to appropriately allocate resources for capacity building. Use of this checklist will allow identification of key areas where trial planning needs to be optimized, as well as helping to identify resources that need to be secured. The CT2S checklist can also serve as a general cell therapy research decision aid to improve research output and accelerate new cell therapy development.

Immune Cell Infiltration into the Brain After Ischemic Stroke in Humans Compared to Mice and Rats: a Systematic Review and Meta-Analysis

Although several studies have suggested that anti-inflammatory strategies reduce secondary infarct growth in animal stroke models, clinical studies have not yet demonstrated a clear benefit of immune modulation in patients. Potential reasons include systematic differences of post-ischemic neuroinflammation between humans and rodents. We here performed a systematic review and meta-analysis to summarize and compare the spatial and temporal distribution of immune cell infiltration in human and rodent stroke. Data on spatiotemporal distribution of immune cells (T cells, macrophages, and neutrophils) and infarct volume were extracted. Data from all rodent studies were pooled by means of a random-effect meta-analysis. Overall, 20 human and 188 rodent stroke studies were included in our analyses. In both patients and rodents, the infiltration of macrophages and neutrophils preceded the lymphocytic influx. Macrophages and neutrophils were the predominant immune cells within 72 h after infarction. Although highly heterogeneously across studies, the temporal profile of the poststroke immune response was comparable between patients and rodents. In rodent stroke, the extent of the immune cell infiltration depended on the duration and location of vessel occlusion and on the species. The density of infiltrating immune cells correlated with the infarct volume. In summary, we provide the first systematic analysis and comparison of human and rodent post-ischemic neuroinflammation. Our data suggest that the inflammatory response in rodent stroke models is comparable to that in patients with stroke. However, the overall heterogeneity of the post-ischemic immune response might contribute to the translational failure in stroke research.

Use of Machine Learning to Re-Assess Patterns of Multivariate Functional Recovery after Fluid Percussion Injury: Operation Brain Trauma Therapy

Traumatic brain injury (TBI) is a leading cause of death and disability. Yet, despite immense research efforts, treatment options remain elusive. Translational failures in TBI are often attributed to the heterogeneity of the TBI population and limited methods to capture these individual variabilities. Advances in machine learning (ML) have the potential to further personalized treatment strategies and better inform translational research. However, the use of ML has yet to be widely assessed in pre-clinical neurotrauma research, where data are strictly limited in subject number. To better establish ML's feasibility, we utilized the fluid percussion injury (FPI) portion of the rich, rat data set collected by Operation Brain Trauma Therapy (OBTT), which tested multiple pharmacological treatments. Previous work has provided confidence that both unsupervised and supervised ML techniques can uncover useful insights from this OBTT pre-clinical research data set. As a proof-of-concept, we aimed to better evaluate the multi-variate recovery profiles afforded by the administration of nine different experimental therapies. We assessed supervised pairwise classifiers trained on a pre-processed data set that incorporated metrics from four feature groups to determine their ability to correctly identify specific drug treatments. In all but one of the possible pairwise combinations of minocycline, levetiracetam, erythropoietin, nicotinamide, and amantadine, the baseline was outperformed by one or more supervised classifiers, the exception being nicotinamide versus amantadine. Further, when the same methods were employed to assess different doses of the same treatment, the ML classifiers had greater difficulty in understanding which treatment each sample received. Our data serve as a critical first step toward identifying optimal treatments for specific subgroups of samples that are dependent on factors such as types and severity of traumatic injuries, as well as informing the prediction of therapeutic combinations that may lead to greater treatment effects than individual therapies.

Pharmacologic Prevention of Myocardial Ischemia-Reperfusion Injury in Patients With Acute Coronary Syndrome Undergoing Percutaneous Coronary Intervention.

Establishing efficient perfusion into the myocardium is the main purpose in patients with acute coronary syndrome, but the process of reperfusion is not without risk and can damage the myocardium paradoxically. Unfortunately, there is no effective treatment for reperfusion injury, and efforts to find an efficient preventive approach are still ongoing. In the past 3 decades, there have been many successful animal studies on how to prevent reperfusion injury; nonetheless, translation to the clinical setting has almost always proven disappointing. In this article, we review clinical studies on the prevention of reperfusion injury in patients with acute coronary syndrome undergoing primary percutaneous coronary intervention in a pharmacologic-based approach. We categorize all the agents that are evaluated for the prevention of myocardial reperfusion injury based on their mechanisms of action into 5 groups: drugs that can reduce oxidative stress, drugs that can affect cellular metabolism, rheological agents that target microvascular obstruction, anti-inflammatory agents, and agents with mixed mechanisms of action. Then, review all the clinical studies of these agents in the setting of primary percutaneous coronary intervention. Finally, we will discuss the possible reasons for the failure in translation of studies into practice and propose potential solutions to overcome this problem.

FEATURES OF USAGE AND TRANSLATION OF STYLISTICALLY MARKED VOCABULARY IN AMERICAN FICTION

The article investigates the usage of stylistically marked vocabulary fiction. The study considers the basic concepts of this linguistic phenomenon, provides a brief classification and characteristics of individual units. It also analyses the main methods of translating stylistically marked vocabulary on the case study of Stephen King's novel. A comparative analysis of the work of Stephen King with its translations into Ukrainian to determine the degree of translation adequacy, as well as to identify various translation transformations when transferring the peculiarities of the stylistically marked vocabulary has been done. In the article, general scientific methods of analysis and synthesis in dividing the issue into its components, and the analysis to determine the meaning of terms has been used. The method of continuous sampling and the analysis of lexical units has also been used in the study. The article considers difficulties that often arise due to differences in social and cultural norms when translating non-standard vocabulary. It has been stated that the degree of correlation between the expression of foreign language and native vocabulary is currently a complex issue. The lexical replacement (partial and complete replacement of the original sing) has been defined as the most common method of translating stylistically marked words. Other methods to be mentioned are a match for a lexical item in the language of translation, euphemistic translation needed to reduce the degree of expression of the original words. In some cases, the replacement of the word of the original with a unit with a coarser expression, based on the context to convey the degree of tension of the speech situation to the reader is used. Translation failures have been considered as well. The most common reasons for unsuccessful translation are the reduction of expression and insufficient consideration of the situational factors of the language, which also leads to an unreasonable underestimation or overestimation of stylistic expression.

Equivalence in Ukrainian-English translation of institutional academic terminology

The article looks into the issue of translation equivalence based on semantic and pragmatic approaches to specialised terminology as used in institutional academic settings. The relations of full, near and partial equivalence and no-equivalence were analysed for pairs of Ukrainian and English terms and semi-terms selected from texts on Ukrainian university sites, representing examples of Ukrainian translation from English. Parallels were made with specialised English institutional terminology used on original British university sites. The material analysed demonstrated a low degree of homogeneity of the two terminological systems resulting from different approaches to understanding the objectives of university tuition, its principles and procedures. Conclusions were drawn as to the translator’s success or failure in achieving equivalence, which was shown to depend on taking into account a number of linguistic and extra-linguistic factors. The importance of semantic structure analysis of terminology in both languages was demonstrated to facilitate the avoidance of translation failures, the task being unduly complex given the absence of comprehensive specialised bilingual dictionaries.

Calculation Method of Underground Cavern Loosening Pressure Based on Limit Analysis Using Upper-Bound Theory and Its Engineering Application

From the point of view of the failure mechanism of the disturbed zone, this paper uses the limit analysis upper-bound theory to analyze the calculation formula of the loosening pressure, distinguish the difference between the vertical pressure and the horizontal pressure in the underground cavern, combine the loosening characteristics of the disturbed zone with the open-type disturbed zone and the annular disturbed zone, and construct the multirigidity slider translation and rotation failure mode to discuss the calculation method of surrounding rock loosening pressure of underground caverns in upper soft and hard rock stratum. The relevant calculation examples are given, and the application of the upper-bound theory of limit analysis is demonstrated in detail. Based on the actual engineering background, the calculation results of the calculation method of the loosening pressure of the cavity based on the upper-bound theory of the limit analysis are analyzed and compared for the different depths and different types of caverns. The difference, rationality, and applicability of the calculation results of this method are analyzed and discussed.

Pragmatic Failure in the Subtitles of Moonlight Movie

<p><strong></strong><em>This paper aims to find out the types of pragmatic failures that can lead to incorrect understanding of meaning by the audience. Pragmatic failure in translation consists of two failures, namely: pragmalinguistic failure and sociopragmatic failure. Pragmalinguistic failures in translation are analyzed using speech act theory proposed by Searle and deixis theory proposed by Levinson. Sociopragmatic failures in translation are analyzed using the principle of cooperation theory proposed by Grice and the principle of politeness theory proposed by Brown and Levinson. The research method used is descriptive qualitative. One hundred seventy-six pragmatic failures are found in the subtitles of Moonlight movie, which is divided into one hundred thirty-six pragmalinguistic failures and forty sociopragmatic failures. Pragmalinguistic failures that occur are the failures to transfer speech acts and deixis of oral speech into subtitles. Sociopragmatic failures that occur are the failures to transfer principle of cooperation of oral speech into subtitles.</em></p>

The Failed Clinical Story of Myostatin Inhibitors against Duchenne Muscular Dystrophy: Exploring the Biology behind the Battle.

Myostatin inhibition therapy has held much promise for the treatment of muscle wasting disorders. This is particularly true for the fatal myopathy, Duchenne Muscular Dystrophy (DMD). Following on from promising pre-clinical data in dystrophin-deficient mice and dogs, several clinical trials were initiated in DMD patients using different modality myostatin inhibition therapies. All failed to show modification of disease course as dictated by the primary and secondary outcome measures selected: the myostatin inhibition story, thus far, is a failed clinical story. These trials have recently been extensively reviewed and reasons why pre-clinical data collected in animal models have failed to translate into clinical benefit to patients have been purported. However, the biological mechanisms underlying translational failure need to be examined to ensure future myostatin inhibitor development endeavors do not meet with the same fate. Here, we explore the biology which could explain the failed translation of myostatin inhibitors in the treatment of DMD.

Translation Initiation Control of RNase E-Mediated Decay of Polycistronic gal mRNA.

In bacteria, mRNA decay is a major mechanism for regulating gene expression. In Escherichia coli, mRNA decay initiates with endonucleolytic cleavage by RNase E. Translating ribosomes impede RNase E cleavage, thus providing stability to mRNA. In transcripts containing multiple cistrons, the translation of each cistron initiates separately. The effect of internal translation initiations on the decay of polycistronic transcripts remains unknown, which we have investigated here using the four-cistron galETKM transcript. We find that RNase E cleaves a few nucleotides (14–36) upstream of the translation initiation site of each cistron, generating decay intermediates galTKM, galKM, and galM mRNA with fewer but full cistrons. Blocking translation initiation reduced stability, particularly of the mutated cistrons and when they were the 5′-most cistrons. This indicates that, together with translation failure, the location of the cistron is important for its elimination. The instability of the 5′-most cistron did not propagate to the downstream cistrons, possibly due to translation initiation there. Cistron elimination from the 5′ end was not always sequential, indicating that RNase E can also directly access a ribosome-free internal cistron. The finding in gal operon of mRNA decay by cistron elimination appears common in E. coli and Salmonella.

Seepage on local stability of slurry trench in deep excavation of diaphragm wall construction

The stability of slurry trench is of importance in diaphragm wall construction. The local stability of slurry trench under seepage application is investigated in this research. In the current research, the local instability of slurry trench is identified as the soil collapse in an instable sublayer and a three-dimensional translational failure mechanism is developed. In this mechanism, the local stability is initialed by the movement of a single rigid block and the seepage application is accounted by introducing the analytical model of semi-confined seepage. The stability is analyzed through kinematic approach and the upper bound solution of safety factor is deduced as a result. The stability is evaluated by optimizing the mechanism for the local failure. Using the current solution, the seepage effect on the stability is analyzed. Regardless of seepage, the stability is mainly dependent on the shear strength of the sublayer. Under seepage application, the failure zone is enlarged and the safety factor decreases as a result. The effect of seepage on the stability is significantly influenced by piezometric head difference Δp and leakage ratio λ of the sublayer. The validity of the current solution is examined by investigating the case of diaphragm wall installation in Suzhou, China.

The 2015 Shenzhen catastrophic landslide in a construction waste dump: analyses of undrained strength and slope stability

The 2015 catastrophic landslide in a 110-m-high waste dump in Shenzhen is recognized as one of the largest landfill failure worldwide. An earlier comprehensive field investigation revealed that the dominant component of the fill was completely decomposed granite (CDG), and the dumping operation was accompanied by a rise of the groundwater level. In this paper, the complex stress paths for the initially unsaturated fill materials being subjected to both rapid filling and wetting were investigated. A simplified method was proposed for estimating the gain of undrained shear strength under the complex stress paths. Soil samples were taken from the site to a laboratory to measure the undrained shear strength and validate the estimation method. Total stress-based stability analyses were carried out to calculate the factor of safety of the dump at failure. The triggering mechanism of the landslide is clarified as follows: The gain of shear strength with the surcharge loading for the wet layer in the lower part of the waste dump was limited by a build-up of excess pore-water pressure. The gain of shear strength for the relatively dry fill material was attenuated with the rise of groundwater level. When the shear strength was not enough to resist the increasing slip force with the surcharge loading, a deep-seated translational failure took place in the lower wet layer of the waste dump. The proposed method for analyses of undrained strength and slope stability are proven to be applicable to the waste-dumping operation with rapid filling and rising groundwater level.