Translational Research Research Articles

Considerations for reporting variants in novel candidate genes identified during clinical genomic testing.

Since the first novel gene discovery for a Mendelian condition was made via exome sequencing (ES), the rapid increase in the number of genes known to underlie Mendelian conditions coupled with the adoption of exome (and more recently, genome) sequencing by diagnostic testing labs has changed the landscape of genomic testing for rare disease. Specifically, many individuals suspected to have a Mendelian condition are now routinely offered clinical ES. This commonly results in a precise genetic diagnosis but frequently overlooks the identification of novel candidate genes. Such candidates are also less likely to be identified in the absence of large-scale gene discovery research programs. Accordingly, clinical laboratories have both the opportunity, and some might argue a responsibility, to contribute to novel gene discovery which should in turn increase the diagnostic yield for many conditions. However, clinical diagnostic laboratories must necessarily balance priorities for throughput, turnaround time, cost efficiency, clinician preferences, and regulatory constraints, and often do not have the infrastructure or resources to effectively participate in either clinical translational or basic genome science research efforts. For these and other reasons, many laboratories have historically refrained from broadly sharing potentially pathogenic variants in novel genes via networks like Matchmaker Exchange, much less reporting such results to ordering providers. Efforts to report such results are further complicated by a lack of guidelines for clinical reporting and interpretation of variants in novel candidate genes. Nevertheless, there are myriad benefits for many stakeholders, including patients/families, clinicians, researchers, if clinical laboratories systematically and routinely identify, share, and report novel candidate genes. To facilitate this change in practice, we developed criteria for triaging, sharing, and reporting novel candidate genes that are most likely to be promptly validated as underlying a Mendelian condition and translated to use in clinical settings.

Citric Acid: A Nexus Between Cellular Mechanisms and Biomaterial Innovations.

Citrate-based biodegradable polymers have emerged as a distinctive biomaterial platform with tremendous potential for diverse medical applications. By harnessing their versatile chemistry, these polymers exhibit a wide range of material and bioactive properties, enabling them to regulate cell metabolism and stem cell differentiation through energy metabolism, metabonegenesis, angiogenesis, and immunomodulation. Moreover, the recent US Food and Drug Administration (FDA) clearance of the biodegradable poly(octamethylene citrate) (POC)/hydroxyapatite-based orthopedic fixation devices represents a translational research milestone for biomaterial science. POC joins a short list of biodegradable synthetic polymers that have ever been authorized by the FDA for use in humans. The clinical success of POC has sparked enthusiasm and accelerated the development of next-generation citrate-based biomaterials. This review presents a comprehensive, forward-thinking discussion on the pivotal role of citrate chemistry and metabolism in various tissue regeneration and on the development of functional citrate-based metabotissugenic biomaterials for regenerative engineering applications.

How preclinical models help to improve outcome in cardiogenic shock.

Preclinical experimentation of cardiogenic shock resuscitation on large animal models represents a powerful tool to decipher its complexity and improve its poor outcome, when small animal models are lacking external validation, and clinical investigation are limited due to technical and ethical constraints. This review illustrates the currently available preclinical models addressing reliably the physiopathology and hemodynamic phenotype of cardiogenic shock, highlighting on the opposite questionable translation based on low severity acute myocardial infarction (AMI) models. Three types of preclinical models replicate reliably AMI-related cardiogenic shock, either with coronary microembolization, coronary deoxygenated blood perfusion or double critical coronary sub-occlusion. These models overcame the pitfall of frequent periprocedural cardiac arrest and offer, to different extents, robust opportunities to investigate pharmacological and/or mechanical circulatory support therapeutic strategies, cardioprotective approaches improving heart recovery and mitigation of the systemic inflammatory reaction. They all came with their respective strengths and weaknesses, allowing the researcher to select the right preclinical model for the right clinical question. AMI-related cardiogenic shock preclinical models are now well established and should replace low severity AMI models. Technical and ethical constraints are not trivial, but this translational research is a key asset to build up meaningful future clinical investigations.

Is it the People or the Place? The Remarkable 30-Year Period of Integrative Physiology Research in the Carlson Gymnasium at the University of Colorado Boulder.

Historically, programs of physical education and sport were housed in gymnasium buildings on academic campuses. As physical education evolved to the more scientifically focused successor departments of exercise science and kinesiology, faculty specialization developed in the physiology of exercise. With time, some faculty broadened their research to study the integrative physiology of other biological states and stressors. Through this series of events, a small group of integrative physiologists formed in the Carlson Gymnasium at the University of Colorado Boulder during the 1990s with the goal of conducting novel biomedical research. The challenges were daunting: no contemporary core laboratory facilities, lack of temperature control, piercing external noise, pests, regular flooding, electrical power outages, and lack of funds for renovation. Despite these obstacles, the group established an innovative program of translational physiological research ranging from high-throughput molecular analyses to cell models to rodent studies to clinical trials in humans. These investigators supported their work with grant awards from the NIH, Department of Defense, NASA, American Heart Association, and private research foundations totaling ~$80M in direct costs from the late 1980s to 2020. Collectively, the faculty and their laboratory personnel published ~950 articles in peer-reviewed scientific journals. Over that period, 379 undergraduate students, 340 graduate students, 84 postdoctoral fellows, and dozens of junior research faculty received scientific training in Carlson, supported by >$21M in extramural funding. What was accomplished by these few integrative physiologists speaks to the importance of the qualities of the investigators rather than their research facilities in determining scientific success.

Scaling neural machine translationto 200 languages.

The development of neural techniques has opened up new avenues for research in machine translation. Today, neural machine translation (NMT) systems can leverage highly multilingual capacities and even perform zero-shot translation, delivering promising results in terms of language coverage and quality. However, scaling quality NMT requires large volumes of parallel bilingual data, which are not equally available for the 7,000+ languages in the world1. Focusing on improving the translation qualities of a relatively small group of high-resource languages comes at the expense of directing research attention to low-resource languages, exacerbating digital inequities in the long run. To break this pattern, here we introduce No Language Left Behind-a single massively multilingual model that leverages transfer learning across languages. We developed a conditional computational model based on the Sparsely Gated Mixture of Experts architecture2-7, which we trained on data obtained with new mining techniques tailored for low-resource languages. Furthermore, we devised multiple architectural and training improvements to counteract overfitting while training on thousands of tasks. We evaluated the performance of our model over 40,000 translation directions using tools created specifically for this purpose-an automatic benchmark (FLORES-200), a human evaluation metric (XSTS) and a toxicity detector that covers every language in our model. Compared with the previous state-of-the-art models, our model achieves an average of 44% improvement in translation quality as measured by BLEU. By demonstrating how to scale NMT to 200 languages and making all contributions in this effort freely available for non-commercial use, our work lays important groundwork for the development of a universal translation system.

Advancing Nitrile-Aminothiol Strategy for Dual and Sequential Bioconjugation.

Nitrile-aminothiol conjugation (NATC) stands out as a promising biocompatible ligation technique due to its high chemo-selectivity. Herein we investigated the reactivity and substrate scope of NAT conjugation chemistry, thus developing a novel pH dependent orthogonal NATC as a valuable tool for chemical biology. The study of reaction kinetics elucidated that the combination of heteroaromatic nitrile and aminothiol groups led to the formation of an optimal bioorthogonal pairing, which is pH dependent. This pairing system was effectively utilized for sequential and dual conjugation. Subsequently, these rapid (≈1 h) and high yield (>90%) conjugation strategies were successfully applied to a broad range of complex biomolecules, including oligonucleotides, chelates, small molecules and peptides. The effectiveness of this conjugation chemistry was demonstrated by synthesizing a fluorescently labelled antimicrobial peptide-oligonucleotide complex as a dual conjugate to imaging in live cells. This first-of-its-kind sequential NATC approach unveils unprecedented opportunities in modern chemical biology, showcasing exceptional adaptability in rapidly creating structurally complex bioconjugates. Furthermore, the results highlight its potential for versatile applications across fundamental and translational biomedical research.

The rhythm of mental health: the relationship of chronotype with psychiatric trait dimensions and diurnal variation in psychiatric symptoms

To advance the emergence of circadian-based therapies, this study characterized how psychiatric symptoms fluctuate across the day and vary between individuals. Using a dimensional approach, we determined how chronotype relates to 13 psychiatric traits, and modeled the temporal development of symptoms throughout the day using generalized additive mixed effects models. In this preregistered study, a subclinical sample completed 13 psychiatric trait scales and a chronotype scale at baseline (N = 515, n = 404 women, 109 men, n = 2 non-binary, M age = 32.4 years, range 18–77), followed by 22 psychiatric symptoms and behaviors rated repeatedly between ~08:00-00:00 (n = 410). Key findings are that 11 out of 13 psychiatric traits were associated with being an evening-type, ranging from depression to obsessive comulsive disorder, social anxiety, and delusional ideation, while only mania was associated with being a morning-type. Four distinct psychiatric trait factors were identified, each predicting worse symptom levels throughout the day. Fatigue-related symptoms exhibited strong time-of-day changes with evening-types experiencing worse fatigue in the morning and morning-types in the evening. Evening-types had considerably lower drive and motivation than morning-types from morning to early evening. Evening-types also had more pronounced negative emotional symptoms and ADHD-type symptoms in the evening, particularly among those high in psychiatric trait factors. These findings identified important research targets that hold promise for improving mental health outcomes, such as strategies to boost morning motivation. Furthermore, the results emphasize the relevance of incorporating circadian factors, including chronotype, into translational psychiatric research and interventions.

American College of Rheumatology White Paper: The Effects of Climate Change on Rheumatic Conditions-An Evolving Landscape and a Path Forward.

Increases in global temperatures and extreme weather events associated with climate change have complex yet poorly understood detrimental impacts on human health. We reviewed the current published literature on climate change-related effects and rheumatic conditions. To summarize our current understanding of the likely effects of climate change, including increased air pollution, on rheumatic disease, we searched the published, peer-reviewed English-language literature from January 2000 to December 2022. Articles were reviewed by a team of rheumatologists and clinical and translational science researchers. Systematic review articles were not included but informed additional literature searches. After extensive examination and adjudication, 88 articles met inclusion criteria and were selected for review. Much of the epidemiologic investigations assessed associations between air pollution and increased risk of development of rheumatoid arthritis, anti-citrullinated protein antibodies, flares of gout, and hospitalizations for systemic lupus erythematosus. Increased heat vulnerability was associated with higher odds of recurrent hospitalizations across rheumatic conditions. Mechanisms for observed associations are poorly understood but could include the effects of epigenetic changes, oxidative stress, and inflammatory cytokines. Studies had limitations, including restricted geography and populations studied without focus on historically marginalized communities at highest risk for adverse effects from pollution and climate change, the relative lack of mechanistic evaluations, and most with only indirect links to climate change. To date, the published literature lacks studies that directly examine effects of climate change on rheumatic diseases. Collaborative translational and epidemiologic research is needed to enhance our understanding and awareness in this area.

Transcriptome Study of 2 BlackCohorts Reveals cis Long Noncoding RNAs Associated With Hypertension-Related mRNAs.

Long noncoding RNAs (lncRNAs) have emerged as critical regulators of the expression of genes involved in cardiovascular diseases. This project aims to identify circulating lncRNAs associated with protein-coding mRNAs differentially expressed between hypertensive and normotensive individuals and establish their link with hypertension. The analyses were conducted in 3 main steps: (1) an unbiased whole blood transcriptome-wide analysis was conducted to identify and replicate protein-coding genes differentially expressed by hypertension status in 497 and 179 Black individuals from the GENE-FORECAST (Genomics, Environmental Factors and the Social Determinants of Cardiovascular Disease in African-Americans Study) and MH-GRID (Minority Health Genomics and Translational Research Bio-Repository Database) studies, respectively. Subsequently, (2) proximal lncRNAs, termed cis lncRNA quantitative trait loci, associated with each mRNA were identified in the GENE-FORECAST study and replicated in the MH-GRID study. Finally, (3) the lncRNA quantitative trait loci were used as predictors in a random forest model to predict hypertension in both data sets. A total of 129 mRNAs were significantly differentially expressed between normotensive and hypertensive individuals in both data sets. The lncRNA-mRNA association analysis revealed 249 cis lncRNA quantitative trait loci associated with 102 mRNAs, including VAMP2 (vesicle-associated membrane protein 2), mitogen-activated protein kinase kinase 3, CCAAT enhancer binding protein beta, and lymphocyte antigen 6 complex, locus E. The 249 lncRNA quantitative trait loci predicted hypertension with an area under the curve of 0.79 and 0.71 in GENE-FORECAST and MH-GRID studies, respectively. This study leveraged a significant sample of Black individuals, a population facing a disproportionate burden of hypertension. The analyses unveiled a total of 271 lncRNA-mRNA relationships involving mRNAs that play critical roles in vascular pathways relevant to blood pressure regulation. The compelling findings, consistent across 2 independent data sets, establish a reliable foundation for designing invitro/in vivo experiments.

Evolving Strategies for Extracellular Vesicles as Future Cardiac Therapeutics: From Macro- to Nano-Applications.

Cardiovascular disease represents the foremost cause of mortality and morbidity worldwide, with a steadily increasing incidence due to the growth of the ageing population. Cardiac dysfunction leading to heart failure may arise from acute myocardial infarction (MI) as well as inflammatory- and cancer-related chronic cardiomyopathy. Despite pharmacological progress, effective cardiac repair represents an unmet clinical need, with heart transplantation being the only option for end-stage heart failure. The functional profiling of the biological activity of extracellular vesicles (EVs) has recently attracted increasing interest in the field of translational research for cardiac regenerative medicine. The cardioprotective and cardioactive potential of human progenitor stem/cell-derived EVs has been reported in several preclinical studies, and EVs have been suggested as promising paracrine therapy candidates for future clinical translation. Nevertheless, some compelling aspects must be properly addressed, including optimizing delivery strategies to meet patient needs and enhancing targeting specificity to the cardiac tissue. Therefore, in this review, we will discuss the most relevant aspects of the therapeutic potential of EVs released by human progenitors for cardiovascular disease, with a specific focus on the strategies that have been recently implemented to improve myocardial targeting and administration routes.

Pharmacological Management of Transthyretin Amyloid Cardiomyopathy: A scoping review.

Transthyretin amyloid cardiomyopathy (ATTR-CM) is characterized by the accumulation of transthyretin (TTR) protein in the myocardium. The aim of this scoping review is to provide a descriptive summary of the clinical trials and observational studies that evaluated the clinical efficacy and safety of various agents used in ATTR-CM, with a goal of identifying the contemporary gaps in literature and to reveal future research opportunities. The search was performed in line with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. A literature search using several databases for observational and clinical trials investigating the treatment modalities for ATTR-CM was undertaken. We extracted data including study characteristics, primary endpoints, and adverse events from each study. A total of 19 studies were included in our scoping review. 8 were clinical trials and 11 were observational analyses. The drugs evaluated included tafamadis, acoramidis, revusiran, TUDCA and doxycycline, diflusinil, inotersan, eplontersen, and patisiran. Tafamidis has shown to be efficacious in the management of ATTR-CM, particularly when initiated at earlier stages. RNA interference and antisense oligonucleotide drugs have shown promising impacts on quality of life. Additionally, this review identified gaps in the literature, particularly among long-term outcomes, comparative effectiveness, and the translation of research into economic contexts. Multiple pharmacological options are potential disease-modifying therapies for ATTR-CM. However, many gaps exist in the understanding of these various drug therapies, warranting further research. The future directions for management of ATTR-CM are promising in regard to improving prognostic implications.

The double empathy problem: A derivation chain analysis and cautionary note.

Work on the "double empathy problem" (DEP) is rapidly growing in academic and applied settings (e.g., clinical practice). It is most popular in research on conditions, like autism, which are characterized by social cognitive difficulties. Drawing from this literature, we propose that, while research on the DEP has the potential to improve understanding of both typical and atypical social processes, it represents a striking example of a weak derivation chain in psychological science. The DEP is poorly conceptualized, and we find that it is being conflated with many other constructs (i.e., reflecting the "jingle-jangle" fallacy). We provide examples to show how this underlies serious problems with translating theoretical claims into empirical predictions and evidence. To start tackling these problems, we propose that DEP research needs reconsideration, particularly through a better synthesis with the cognitive neuroscience literature on social interaction. Overall, we argue for a strengthening of the derivation chain pertaining to the DEP, toward more robust research on (a)typical social cognition. Until then, we caution against the translation of DEP research into applied settings. (PsycInfo Database Record (c) 2024 APA, all rights reserved).

The division of rare diseases research innovation at the national center for advancing translational sciences, NIH: mission, history, and current research activities

The mission of the NCATS Division of Rare Diseases Research Innovation (DRDRI), formerly known as the Office of Rare Diseases Research, is to advance rare diseases research to benefit patients. DRDRI is part of the National Center for Advancing Translational Sciences, one of the 27 components of the US National Institutes of Health. DRDRI facilitates and coordinates NIH-wide activities involving rare diseases research, as well as directly supporting rare diseases research activities. These activities include the development and maintenance of a centralized database on rare diseases; collaboration and coordination with organizations focused on orphan products development and rare diseases research across the globe, advising the Office of the NIH Director on matters related to NIH-sponsored research involving rare diseases; and responding to information and policy requests about rare diseases within the NIH. DRDRI also supports various rare diseases research activities, including the Rare Diseases Clinical Research Network, rare disease-related conference grants, and assessment of the costs of untreated rare diseases. In addition, several of the projects DRDRI is supporting are “many diseases at a time” translational approaches for rare diseases, which emphasize leveraging commonalities across multiple rare diseases. These include the support of “basket trials” based on shared molecular etiologies across multiple rare diseases, as well as therapeutic platforms for the treatment of monogenic diseases, such as gene therapy and genome editing. This Perspective will provide an overview and summary of these various activities, noting where relevant our collaborative partnerships within the U.S. and internationally.

DIFFERENTIATION OF WORD MEANINGS IN TRANSLATION (ON THE EXAMPLE OF RUSSIAN AND TURKISH LANGUAGES)

The relevance of the study of lexical transformations in the process of translation is associated with the need to ensure communication between the author and recipients in terms of recreating the lexical, structural and stylistic richness of the original in the translated text. Since today far from all the methods and mechanisms for eliminating language inaccuracies have been studied, this direction occupies an important role in the translation science branch of knowledge. The purpose of the study is to examine the role and functions of differentiation of meanings in the process of literary translation from Russian into Turkish by analysing the lexico-semantic means used in the context of literary works. This paper uses the methods of contextual, lexico-semantic, comparative, linguoculturological and analytical-synthetic analysis are used in the paper. This study is aimed at studying lexical transformations in the translated text, mechanisms for transferring the semantic subtleties of the source with minimization of lexical losses and combining techniques to obtain a translated text that is as accessible to the readership as possible. The work is focused on contextual and lexico-semantic analysis, search, and comparison of lexical variants and structural patterns in the original and translation. Attention was drawn to the mechanisms of differentiation and generalization of meanings, as well as the semantic unfolding of events. When analysing lexico-semantic and syntactic constructions, as well as phraseological phrases, the topic of national linguistic features and cultural specifics, which play an important role in the translation of literary texts, was touched upon. In the future, this work can be used in the field of translation studies, cultural linguistics, automatic text processing, the creation of lexicographic thesauri, and the study of semantic patterns and equivalents. The study examined the nuances of word usage in translations from Russian to Turkish, underscoring the inevitability of lexical transformations. Strategies primarily involved expanding, narrowing, and clarifying the source text’s semantics. Russian-Turkish translations also frequently employed semantic deployment and structural element transformations to elucidate intricate meanings. Stable, often phraseological turns were highlighted, emphasizing their non-equivalent nature. Such techniques reconstruct the original’s cultural essence and authorial style. While there exist discrepancies between the Russian and Turkish contexts, lexical transformations often simplify complex structures for clarity in Turkish. Idiomatic expressions in Turkish involve detailing meanings or unfolding specific events descriptively. The study demonstrated the interplay between the original and its translation, revealing strategies and issues within linguistics and translation studies.

Evaluating the impact of translational research enrollment on the patient care experience of Veterans with prostate cancer who receive care through the Veterans Affairs (VA) healthcare system.

e23210 Background: Veterans with cancer represent a unique subset of patients with distinct exposure histories and cancer epidemiology. Translational research studies that incorporate Veteran-derived biospecimens are therefore critical to advance our understanding of Veteran cancer biology and improve treatment options for Veterans with cancer. Biospecimen-based translational studies also offer an opportunity to enhance the Veteran care experience by enabling Veterans to directly contribute to cancer research efforts. While the biologic benefits of biospecimen research have been well established, the benefit of translational research on the Veteran care experience has yet to be defined. In this study, we evaluated: 1. Whether Veteran enrollment in a biospecimen-based prostate cancer research study improved their VA patient care experience and satisfaction and 2. Whether a VA-based data analyst tool could be used to optimize patient enrollment in translational research studies. Methods: Beginning in January, 2022, Veterans with a diagnosis of prostate cancer receiving care at the William S. Middleton VA were enrolled in a translational research study that collected blood and tissue biospecimens for subsequent investigation and analysis. After at least 30 days of enrollment, subjects were sent an anonymous survey inquiring about how participation in the translational research study impacted their VA care experience and healthcare satisfaction. To optimize enrollment in the study, an ICD-9 code search function was employed within the medical record database to readily identify eligible VA clinic patients based on an active prostate cancer diagnosis. Descriptive analyses were performed using Prism statistical software. Results: Nearly all Veterans who responded to the questionnaire agreed that participation in translational research was a meaningful experience that increased their satisfaction with their VA medical care. In addition, a vast majority of Veterans surveyed felt that their research participation could help improve care for other Veterans, and most expressed willingness to participate in future VA research opportunities. In a secondary analysis, our ICD-9 search function accurately identified eligible VA clinic patients with a prostate cancer diagnosis, and implementation of this tool has saved approximately 30 minutes of weekly physician and research coordinator work compared to manual chart review. Conclusions: Veteran enrollment in translational research studies provides a meaningful experience for Veterans that can lead to increased satisfaction with the VA healthcare system. Future VA initiatives to improve the Veteran care experience should focus on expanding translational research opportunities for Veterans as well as addressing potential barriers to enrollment.

The Development of Robust Antibodies to Sarcospan, a Dystrophin- and Integrin-Associated Protein, for Basic and Translational Research.

Sarcospan (SSPN) is a 25-kDa transmembrane protein that is broadly expressed at the cell surface of many tissues, including, but not limited to, the myofibers from skeletal and smooth muscles, cardiomyocytes, adipocytes, kidney epithelial cells, and neurons. SSPN is a core component of the dystrophin-glycoprotein complex (DGC) that links the intracellular actin cytoskeleton with the extracellular matrix. It is also associated with integrin α7β1, the predominant integrin expressed in skeletal muscle. As a tetraspanin-like protein with four transmembrane spanning domains, SSPN functions as a scaffold to facilitate protein-protein interactions at the cell membrane. Duchenne muscular dystrophy, Becker muscular dystrophy, and X-linked dilated cardiomyopathy are caused by the loss of dystrophin at the muscle cell surface and a concomitant loss of the entire DGC, including SSPN. SSPN overexpression ameliorates Duchenne muscular dystrophy in the mdx murine model, which supports SSPN being a viable therapeutic target. Other rescue studies support SSPN as a biomarker for the proper assembly and membrane expression of the DGC. Highly specific and robust antibodies to SSPN are needed for basic research on the molecular mechanisms of SSPN rescue, pre-clinical studies, and biomarker evaluations in human samples. The development of SSPN antibodies is challenged by the presence of its four transmembrane domains and limited antigenic epitopes. To address the significant barrier presented by limited commercially available antibodies, we aimed to generate a panel of robust SSPN-specific antibodies that can serve as a resource for the research community. We created antibodies to three SSPN protein epitopes, including the intracellular N- and C-termini as well as the large extracellular loop (LEL) between transmembrane domains 3 and 4. We developed a panel of rabbit antibodies (poly- and monoclonal) against an N-terminal peptide fragment of SSPN. We used several assays to show that the rabbit antibodies recognize mouse SSPN with a high functional affinity and specificity. We developed mouse monoclonal antibodies against the C-terminal peptide and the large extracellular loop of human SSPN. These antibodies are superior to commercially available antibodies and outperform them in various applications, including immunoblotting, indirect immunofluorescence analysis, immunoprecipitation, and an ELISA. These newly developed antibodies will significantly improve the quality and ease of SSPN detection for basic and translational research.

Genomic Characterization of Preclinical Prostate Cancer Cell Line Models.

As we move into the era of precision medicine, the growing relevance of genetic alterations to prostate cancer (PCa) development and treatment demonstrates the importance of characterizing preclinical models at the genomic level. Our study investigated the genomic characterization of eight PCa cell lines to understand which models are clinically relevant. We designed a custom AmpliSeq DNA gene panel that encompassed key molecular pathways targeting AR signaling, apoptosis, DNA damage repair, and PI3K/AKT/PTEN, in addition to tumor suppressor genes. We examined the relationship between cell line genomic alterations and therapeutic response. In addition, using DepMap's Celligner tool, we identified which preclinical models are most representative of specific prostate cancer patient populations on cBioPortal. These data will help investigators understand the genetic differences in preclinical models of PCa and determine which ones are relevant for use in their translational research.

A comprehensive review on the pharmacological prospects of Terpinen-4-ol: From nature to medicine and beyond

Owing to their extensive biological potential, essential oils (EOs) and their bioactive phytochemicals have gained attention from the scientific community. Within this domain, Terpinen-4-ol (T-4-ol), a bioactive monoterpene alcohol and the major constituent of tea tree oil (TTO), has made its way into translational research. Recent literature on T-4-ol strongly indicates its diverse pharmacological properties, including but not limited to antimicrobial, antivirulent, anti-oxidant, anti-inflammatory, anti-hypertensive, and anti-cancer effects. Hence, this review is the first to provide a comprehensive overview of the sources, bioavailability, safety, pharmaceutical delivery systems, and multifaceted biological properties of T-4-ol, emphasizing its medicinal potential for widescale application. The antibacterial and antifungal effectiveness of T-4-ol has been discussed, encompassing its role in combating a broad spectrum of bacterial and fungal pathogens. The review delves into the antivirulent prospects of T-4-ol, shedding light on its ability to attenuate virulence and mitigate bacterial pathogenesis. Scientific literature on the anti-oxidant and anti-inflammatory activity of T-4-ol highlighting its role in neutralizing reactive oxygen species and modulating inflammatory pathways has also been collated. Furthermore, the review elaborates on the cardioprotective and anti-hypertensive properties of T-4-ol and augments literature on its anti-cancer mechanism against various cancer cell lines. The review also provides in-depth knowledge of the pharmaceutical formulations of T-4-ol and recent knowledge about its application in clinical/field trials. The exploration of these diverse attributes positions T-4-ol as a promising candidate for further research and therapeutic repurposing in various biomedical applications.

Translational research in punishment learning.

Punishment learning is learning of the causal relationship between responses and their adverse or undesirable consequences. Here, we review our translational approach for understanding whether, when, and how individuals differ in what they learn during punishment, and how these differences in learning may drive persistent poor or maladaptive decisions. We show that individual differences in punishment insensitivity can emerge from differences between individuals in what they learn about punishment (instrumental contingency knowledge), rather than differences in aversive valuation, reward valuation, general (impulsivity), or specific (habit) behavioral control. These differences in instrumental contingency knowledge are shared with and can be studied in other animals. Our approach has strong construct and predictive validity, providing a robust translational platform for studying how punishment learning and decision making may contribute to neuropsychiatric disorders. (PsycInfo Database Record (c) 2024 APA, all rights reserved).

Creating and establishing a sustainable culture of clinical and translational research at an academic cancer center.

e23220 Background / Objectives: At the Ellis Fischel Cancer Center (EFCC) at the Univ. of Missouri (MU) School of Medicine (SOM), our recent (2016 - 2020) accurals to interventional oncology clinical trials (CT) have been suboptimal. Hence, the EFCC research leadership undertook a number of initiatives since 2021 to improve the function and productivity of the oncology CT enterprise. The objective of our retrospective review was to determine the impact of our initiatives including improving enrollments to clinical trials. Methods: These major programmatic initiatives have included the following: (1) CT portfolio analysis; (2) faculty survey to assess concerns/ needs related to enrollment; (3) Development of a "One-Pager" list of open CT; (4) Working with faculty leader "champions"; (5) Increasing the number of clinical research staff; (6) Initiation of a monthly "Clinical Trials Working Group (CTWG)" to monitor enrollment to clinical trials, troubleshooting obstacles to accruals and on-going CT portfolio analysis and adjustments; (7) Development of multi-disciplinary "Disease Working Groups" (DWGs) in Breast, GU, GYN-Onc., Lung, GI and CNS cancers to establish a Protocol Review & Monitoring System (PRMS) with the objective of aligning our clinical trials with our patient population; (9) Initiation of a monthly “Investigator Education Workshop” (IEW) to educate our faculty on the conduct of investigator initiated CT and pharma sponsored CT; (10) Initiation of a "Top Enrolling Ceremony" to honor the top enrollers to clinical trials. Results: The analysis of our CT portfolio revealed that in both December 2020 and May 2021, more than half [i.e., 52% (n = 17/33 and n = 13/25, respectively] of our CT had never enrolled a patient in the lifetime of the protocol. Since the implementation of the PRMS in late 2021, we have observed a continual decrease in the status of those clinical trials with “never” any enrollments from a historical average of 52% to 34% in January 2022, to 32% in January 2023 and to 28% in October 2023, p = 0.0173. In addition, implementation of the PRMS also had an immediate significant impact such that only 53% of all of the protocols reviewed by the Protocol Review and Monitoring Committee were approved in 2021 vs. a historical average of 75% from 2018 - 2020. Moreover, between 2021 and 2023, an average total of 82 patients were enrolled to interventional oncology clinical trials vs. the historical average of 42 patients per year from 2016- 2020, representing an overall increase of 95% p = 0.0004. Conclusions: The development and establishment of the PRMS within the last 3 years has had a very positive impact on our clinical trial enterprise at the EFCC by reducing active clinical trials that are not suitable for our patient population and significantly increasing our enrollment to interventional oncology clinical trials. For 2024, we will continue our implementation of the PRMS at the EFCC.