Prospective prediction of plasma pharmacokinetics of a novel immune-modulating agent in cancer patients after intra-tumoral administration: translation from non-clinical species to humans.

Intra-tumoral (I-TUMOUR) delivery is being widely explored for novel anti-cancer agents. This route is anticipated to result in high tumour concentrations leading to better efficacy and safety. Prediction of human systemic pharmacokinetics (PK) from non-clinical species facilitates understanding of pharmacokinetic-pharmacodynamic relationships, efficient dose selection, and risk assessment of novel drugs. However, there is limited knowledge on the predictability of human pharmacokinetics following I-TUMOUR delivery.In this publication, we present a case study wherein human systemic PK of a novel agent administered intra-tumourally was prospectively predicted and compared with observed human PK.Simple allometry was used to project the human clearance (10.5 mL/min/kg) and steady-state volume of distribution (1.4 L/kg) after intravenous (IV) dosing. Using these IV PK parameters and assuming rapid absorption and complete I-TUMOUR bioavailability, human plasma PK profile was simulated. The projected 30 min concentrations and AUC(0-6h) were within 1.9 to 2.5-fold and 1 to 1.4-fold of the observed PK indicating a reasonable concordance between predicted and observed PK.To our knowledge, this is the first article that prospectively projected human pharmacokinetics after I-TUMOUR dosing. The results from this study indicate that similar approaches can be used to project the human PK of other I-TUMOUR agents.

Intravitreal Pharmacokinetics in Mice: SPECT/CT Imaging and Scaling to Rabbits and Humans.

Preclinical in vivo tests of retinal drug responses are carried out in mice and rats, often after intravitreal injections. However, quantitative pharmacokinetics in the mouse eye is poorly understood. Ocular pharmacokinetics studies are usually done in rabbits. We investigated elimination of three compounds ([99mTc]Tc-pentetate, [111In]In-pentetreotide, [99mTc]Tc-human serum albumin with molecular weights of 510.2 Da, 1506.4 Da, and 66.5 kDa, respectively) from mouse vitreous using imaging with single photon emission computed tomography/computed tomography (SPECT/CT). Increasing molecular weight decreased elimination of the compounds from the mouse eyes. Half-lives of [99mTc]Tc-pentetate, [111In]In-pentetreotide, and [99mTc]Tc-human serum albumin in the mouse eyes were 1.8 ± 0.5 h, 4.3 ± 1.7 h, and 30.0 ± 9.0 h, respectively. These values are 3-12-fold shorter than half-lives of similar compounds in the rabbit vitreous. Dose scaling factors were calculated for mouse-to-rabbit and mouse-to-man translation. They were 27-90 and 38-126, respectively, for intravitreal injections in rabbit and man. We show ocular pharmacokinetic parameters for mice and interspecies scaling factors that may augment ocular drug discovery and development.

Transcriptome analysis of distinct mouse strains reveals kinesin light chain-1 splicing as an amyloid-ß accumulation modifier.

Alzheimer's disease (AD) is characterized by the accumulation of amyloid-ß (Aß). The genes that govern this process, however, have remained elusive. To this end, we combined distinct mouse strains with transcriptomics to directly identify disease-relevant genes. We show that AD model mice (APP-Tg) with DBA/2 genetic backgrounds have significantly lower levels of Aß accumulation compared with SJL and C57BL/6 mice. We then applied brain transcriptomics to reveal the genes in DBA/2 that suppress Aß accumulation. To avoid detecting secondarily affected genes by Aß, we used non-Tg mice in the absence of Aß pathology and selected candidate genes differently expressed in DBA/2 mice. Additional transcriptome analysis of APP-Tg mice with mixed genetic backgrounds revealed kinesin light chain-1 (Klc1) as an Aß modifier, indicating a role for intracellular trafficking in Aß accumulation. Aß levels correlated with the expression levels of Klc1 splice variant E and the genotype of Klc1 in these APP-Tg mice. In humans, the expression levels of KLC1 variant E in brain and lymphocyte were significantly higher in AD patients compared with unaffected individuals. Finally, functional analysis using neuroblastoma cells showed that overexpression or knockdown of KLC1 variant E increases or decreases the production of Aß, respectively. The identification of KLC1 variant E suggests that the dysfunction of intracellular trafficking is a causative factor of Aß pathology. This unique combination of distinct mouse strains and model mice with transcriptomics is expected to be useful for the study of genetic mechanisms of other complex diseases.

Artificial intelligence and human translation: A contrastive study based on legal texts.

Artificial intelligence has advanced significantly in recent years, affecting multiple aspects of life. In particular, this has had an impact on the machine translation of texts, reducing or removing human interaction. Artificial intelligence (AI)-based translation software models have thus become widely available, and these now include Google Translate, Bing, Microsoft Translator, DeepL, Reverso, Systran Translate, and Amazon Translate. Several computer-aided translation (CAT) tools such as Memoq, Trados, Smartcat, Lokalise, Smartling, Crowdin, TextUnited, and Memsource are also available. More recently, artificial intelligence has been applied in the development of applications such as ChatGPT, ChatSonic, GPT-3 Playground, Chat GPT 4 and YouChat, which simulate conversational responses to researchers' inquiries, mimicking human interactions more directly. This study thus aimed to examine any remaining contrasts between human and AI translation in the legal field to investigate the potential hypothesis that there is now no difference between human and AI translation. The paper thus also examined concerns about whether the need for human translators will decline in the face of AI development, as well as beginning to assess whether it will ever be possible for those in the legal field to depend only on machine translation. To achieve this, a collection of legal texts from various contracts was chosen, and these pieces were both allocated to legal translators and subjected to AI translation systems. Using a contrastive methodology, the study thus examined the differences between AI and human translation, examining the strengths and weaknesses of both approaches and discussing the situations in which each approach might be most effective.

A systematic review of animal and human data comparing the nasal potential difference test between cystic fibrosis and control.

The nasal potential difference test (nPD) is an electrophysiological measurement which is altered in patients and animal models with cystic fibrosis (CF). Because protocols and outcomes vary substantially between laboratories, there are concerns over its validity and precision. We performed a systematic literature review (SR) of the nPD to answer the following review questions: A. Is the nasal potential difference similarly affected in CF patients and animal models?", and B. "Is the nPD in human patients and animal models of CF similarly affected by various changes in the experimental set-up?". The review protocol was preregistered on PROSPERO (CRD42021236047). We searched PubMed and Embase with comprehensive search strings. Two independent reviewers screened all references for inclusion and extracted all data. Included were studies about CF which described in vivo nPD measurements in separate CF and control groups. Risk of bias was assessed, and three meta-analyses were performed. We included 130 references describing nPD values for CF and control subjects, which confirmed substantial variation in the experimental design and nPD outcome between groups. The meta-analyses showed a clear difference in baseline nPD values between CF and control subjects, both in animals and in humans. However, baseline nPD values were, on average, lower in animal than in human studies. Reporting of experimental details was poor for both animal and human studies, and urgently needs to improve to ensure reproducibility of experiments within and between species.

Comparing translational success rates across medical research fields - A combined analysis of literature and clinical trial data.

Many interventions that show promising results in preclinical development do not pass clinical tests. Part of this may be explained by poor animal-to-human translation. Using animal models with low predictability for humans is neither ethical nor efficient. If translational success shows variation between medical research fields, analyses of common practices in these fields could identify factors contributing to successful translation. We assessed translational success rates in medical research fields using two approaches: through literature and clinical trial registers. Literature: We comprehensively searched PubMed for pharmacology, neuroscience, cancer research, animal models, clinical trials, and translation. After screening, 117 review papers were included in this scoping review. Translational success rates were not different within pharmacology (72%), neuroscience (62%), and cancer research (69%). Clinical trials: The fraction of phase-2 clinical trials with a positive outcome was used as a proxy (i.e., an indirect resemblance measure) for translational success. Trials were retrieved from the WHO trial register and categorized into medical research fields following the international classification of disease (ICD-10). Of the phase-2 trials analyzed, 65.2% were successful. Fields with the highest success rates were disorders of lipoprotein metabolism (86.0%) and epilepsy (85.0%). Fields with the lowest success rates were schizophrenia (45.4%) and pancreatic cancer (46.0%). Our combined analyses suggest relevant differences in success rates between medical research fields. Based on the clinical trials, comparisons of practice, e.g., between epilepsy and schizophrenia, might identify factors that influence translational success.

Modeling Brain Dysconnectivity in Rodents.

Altered or atypical functional connectivity as measured with functional magnetic resonance imaging (fMRI) is a hallmark feature of brain connectopathy in psychiatric, developmental, and neurological disorders. However, the biological underpinnings and etiopathological significance of this phenomenon remain unclear. The recent development of MRI-based techniques for mapping brain function in rodents provides a powerful platform to uncover the determinants of functional (dys)connectivity, whether they are genetic mutations, environmental risk factors, or specific cellular and circuit dysfunctions. Here, we summarize the recent contribution of rodent fMRI toward a deeper understanding of network dysconnectivity in developmental and psychiatric disorders. We highlight substantial correspondences in the spatiotemporal organization of rodent and human fMRI networks, supporting the translational relevance of this approach. We then show how this research platform might help us comprehend the importance of connectional heterogeneity in complex brain disorders and causally relate multiscale pathogenic contributors to functional dysconnectivity patterns. Finally, we explore how perturbational techniques can be used to dissect the fundamental aspects of fMRI coupling and reveal the causal contribution of neuromodulatory systems to macroscale network activity, as well as its altered dynamics in brain diseases. These examples outline how rodent functional imaging is poised to advance our understanding of the bases and determinants of human functional dysconnectivity.

The impact of translation modality on user experience: an eye-tracking study of the Microsoft Word user interface.

This paper presents results of the effect of different translation modalities on users when working with the Microsoft Word user interface. An experimental study was set up with 84 Japanese, German, Spanish, and English native speakers working with Microsoft Word in three modalities: the published translated version, a machine translated (MT) version (with unedited MT strings incorporated into the MS Word interface) and the published English version. An eye-tracker measured the cognitive load and usability according to the ISO/TR 16982 guidelines: i.e., effectiveness, efficiency, and satisfaction followed by retrospective think-aloud protocol. The results show that the users' effectiveness (number of tasks completed) does not significantly differ due to the translation modality. However, their efficiency (time for task completion) and self-reported satisfaction are significantly higher when working with the released product as opposed to the unedited MT version, especially when participants are less experienced. The eye-tracking results show that users experience a higher cognitive load when working with MT and with the human-translated versions as opposed to the English original. The results suggest that language and translation modality play a significant role in the usability of software products whether users complete the given tasks or not and even if they are unaware that MT was used to translate the interface.

Interactions Between Genes From Aging Pathways May Influence Human Lifespan and Improve Animal to Human Translation.

A major goal of aging research is identifying genetic targets that could be used to slow or reverse aging - changes in the body and extend limits of human lifespan. However, majority of genes that showed the anti-aging and pro-survival effects in animal models were not replicated in humans, with few exceptions. Potential reasons for this lack of translation include a highly conditional character of genetic influence on lifespan, and its heterogeneity, meaning that better survival may be result of not only activity of individual genes, but also gene-environment and gene-gene interactions, among other factors. In this paper, we explored associations of genetic interactions with human lifespan. We selected candidate genes from well-known aging pathways (IGF1/FOXO growth signaling, P53/P16 apoptosis/senescence, and mTOR/SK6 autophagy and survival) that jointly decide on outcomes of cell responses to stress and damage, and so could be prone to interactions. We estimated associations of pairwise statistical epistasis between SNPs in these genes with survival to age 85+ in the Atherosclerosis Risk in Communities study, and found significant (FDR < 0.05) effects of interactions between SNPs in IGF1R, TGFBR2, and BCL2 on survival 85+. We validated these findings in the Cardiovascular Health Study sample, with P < 0.05, using survival to age 85+, and to the 90th percentile, as outcomes. Our results show that interactions between SNPs in genes from the aging pathways influence survival more significantly than individual SNPs in the same genes, which may contribute to heterogeneity of lifespan, and to lack of animal to human translation in aging research.

Improving Translation by Identifying Evidence for More Human-Relevant Preclinical Strategies.

Preclinical animal studies are performed to analyse the safety and efficacy of new treatments, with the aim to protect humans. However, there are questions and concerns about the quality and usefulness of preclinical animal research. Translational success rates vary between 0 and 100%, and no clear relationship has been found with possible predictive factors such as animal species or field of research. Therefore, it is not yet possible to indicate what factors predict successful translation. Translational strategies were therefore discussed at an international conference held in the Netherlands in November 2019, aiming to develop practical guidelines for more robust animal-to-human translation. The conference was organised during the course of a research project funded by the Dutch Research Council (313-99-310), addressing possible solutions for the low translational values that had been published for a multitude of animal studies in human health care. This article provides an overview of the project and the conference discussions. Based on the conference results and the findings from the research project, we define four points of attention that are crucial in the search for improved translational success rates: (a) optimising the methods and design of studies; (b) incorporation of the complexity of the human patient in research; (c) start with the patient rather than existing animal models as the gold standard; and (d) more and better collaboration within the chain from funding to pharmacy. We conclude that this requires improved organization and use of procedures, as well as a change of attitude and culture in research, including a consideration of the translational value of animal-free innovations and human-relevant science.

A Systematic Review Comparing Experimental Design of Animal and Human Methotrexate Efficacy Studies for Rheumatoid Arthritis: Lessons for the Translational Value of Animal Studies.

Increased awareness and understanding of current practices in translational research is required for informed decision making in drug development. This paper describes a systematic review of methotrexate for rheumatoid arthritis, comparing trial design between 147 animal and 512 human studies. Animal studies generally included fewer subjects than human studies, and less frequently reported randomisation and blinding. In relation to life span, study duration was comparable for animals and humans, but included animals were younger than included humans. Animal studies often comprised males only (61%), human studies always included females (98% included both sexes). Power calculations were poorly reported in both samples. Analyses of human studies more frequently comprised Chi-square tests, those of animal studies more frequently reported analyses of variance. Administration route was more variable, and more frequently reported in animal than human studies. Erythrocyte sedimentation rate and c-reactive protein were analysed more frequently in human than in animal studies. To conclude, experimental designs for animal and human studies are not optimally aligned. However, methotrexate is effective in treating rheumatoid arthritis in animal models and humans. Further evaluation of the available evidence in other research fields is needed to increase the understanding of translational success before we can optimise translational strategies.

Safety testing of monoclonal antibodies in non-human primates: Case studies highlighting their impact on human risk assessment.

Monoclonal antibodies (mAbs) are improving the quality of life for patients suffering from serious diseases due to their high specificity for their target and low potential for off-target toxicity. The toxicity of mAbs is primarily driven by their pharmacological activity, and therefore safety testing of these drugs prior to clinical testing is performed in species in which the mAb binds and engages the target to a similar extent to that anticipated in humans. For highly human-specific mAbs, this testing often requires the use of non-human primates (NHPs) as relevant species. It has been argued that the value of these NHP studies is limited because most of the adverse events can be predicted from the knowledge of the target, data from transgenic rodents or target-deficient humans, and other sources. However, many of the mAbs currently in development target novel pathways and may comprise novel scaffolds with multi-functional domains; hence, the pharmacological effects and potential safety risks are less predictable. Here, we present a total of 18 case studies, including some of these novel mAbs, with the aim of interrogating the value of NHP safety studies in human risk assessment. These studies have identified mAb candidate molecules and pharmacological pathways with severe safety risks, leading to candidate or target program termination, as well as highlighting that some pathways with theoretical safety concerns are amenable to safe modulation by mAbs. NHP studies have also informed the rational design of safer drug candidates suitable for human testing and informed human clinical trial design (route, dose and regimen, patient inclusion and exclusion criteria and safety monitoring), further protecting the safety of clinical trial participants.

The Induction of Bone Formation: The Translation Enigma.

A paradigmatic shift in the way of thinking is what bone tissue engineering science requires to decrypt the translation conundrum from animal models into human. The deductive work of Urist (1965), who discerned the principle of bone induction from the pioneering works of Senn, Huggins, Lacroix, Levander, and other bone regenerative scientists, provided the basis that has assisted future bone tissue regenerative scientists to extend the bone tissue engineering field and its potential uses for bone regenerative medicine in humans. However, major challenges remain that are preventing the formation of bone by induction clinically. Growing experimental evidence is indicating that bone inductive studies are non-translatable from animal models into a clinical environment. This is preventing bone tissue engineering from reaching the next phase in development. Countless studies are trying to discern how the formation of bone by induction functions mechanistically, so as to try and solve this enigmatic problem. However, are the correct questions being asked? Why do bone inductive animal studies not translate into humans? Why do bone induction principles not yield the same extent of bone formation as an autogenous bone graft? What are bone tissue engineering scientists missing? By critically re-assessing the past and present discoveries of the bone induction field, this review article attempts to re-discover the field of bone formation by induction, identifying some key features that may have been missed. These include a detailed library of all proteins in bones and their arrangement in the 3D superstructure of the bone together with some other important criteria not considered by tissue engineering scientists. The review therefore not only re-iterates possible avenues of research that need to be re-explored but also seeks to guide present and future scientists in how they assess their own research in light of experimental design and results. By addressing these issues bone formation by induction without autografts might finally become clinically viable.

Translating dynamic defense patterns from rodents to people.

Specific defensive behaviors of rodents are shaped by features of the eliciting threat stimuli and situation. Threat scenarios confirmed these relationships in people, with results substantially replicated in 4 additional scenario studies. Subsequent human studies involve computer games measuring fear as flight from threat stimuli and anxiety as alternation between two threats. Stabilometric studies have shown reduction in sway (freezing) to inescapable (e.g. with gun pointed at subject) threatening photographs; but enhanced lateral sway (flight attempts) to escapable threats; (gun pointed away from subject). Relationships between threat ambiguity, risk assessment, and anxiety have been validated by identification of videos of facial expressions to ambiguous threats, as anxiety; and systematic biases toward threat stimuli by anxious individuals. Enhanced rumination, interpretable as unsuccessful risk assessment, is a dynamic component of both anxiety and depression, particularly in women. While there is less experimental work on defensive threat/attack, a transdiagnostic "Fear of Harm" phenotype of aggression associated with fear suggests that this is a component of pathological as well as normal human defensive behavior.

A Functional Role for the Monomethylated Gln-51 and Lys-53 Residues of the 49GGQTK53 Motif of eL42 from Human 80S Ribosomes.

BACKGROUND: We have previously demonstrated that the eukaryote-specific ribosomal protein eL42 of the human 80S ribosome contains seven monomethylated residues, among which are the Gln-51 and Lys-53 residues contained in the 47GFGGQTK53 sequence conserved in all eukaryotic 80S ribosomes. This sequence contains the methylated and universally conserved GGQ motif common for all class-1 translation termination factors responsible for stop codon recognition and for triggering the hydrolysis of the P site-bound peptidyl-tRNA. We have also recently reported a model of ribosomal ternary eL42-tRNA-eRF1 complex where specific regions of all three macromolecules (the comparably flexible GGQ domains of eRF1 and eL42 and the CCA-arm of tRNA) are involved in interactions. METHOD: Here, we have studied the interactions between recombinant eL42 and eRF1 proteins and the tRNA substrate by means of the Biacore assay, using the wild-type eL42 protein, the eL42-Δ(GGQTK) mutant (the eL42 protein whose GGQTK motif has been deleted), the single Q51E and K53Q mutants (eL42-Q51E and eL42-K53Q, respectively), as well as the double Q51A/K53A mutant (eL42-Q51A/K53A). RESULTS: Our results show that the monomethylated Gln-51 and Lys-53 residues contained in the 47GFGGQTK53 sequence of eL42 and the monomethylated GGQ motif of eRF1 represents the sites of interaction between these two proteins through hydrophobic contacts between methyl groups. We also demonstrate that the interactions between eL42 and tRNA or 28S rRNA are characterized by strong binding affinities (KD values in the nanomolar or picomolar range, respectively) which argue for specific interactions. Strong interactions between eL42 and tRNA are likely to be responsible for the decrease in the poly(U)-dependent poly(Phe) synthesis activity of human 80S or E. coli 70S ribosomes in the presence of added human recombinant eL42. It is proposed that the decrease of the activity of the ribosome is caused by the sequestration of the substrate Phe-tRNAPhe by the added eL42 protein. CONCLUSION: Interactions between the monomethylated Gln-51 and Lys-53 residues of the 49GGQTK53 motif of the human eL42 protein and the methylated GGQ motif of eRF1 are likely to play a functional role on translating human 80S ribosomes.