Translational Research Research Articles

Abstract C172: Diversifying translational research models to address outcomes disparities in lung cancer

Abstract Introduction: Racial disparities in lung cancer remains a persistent and challenging problem, with African Americans experiencing the highest mortality of any race or ethnic group. Emerging evidence suggests that multiple biological factors affect the development and progression of lung cancer. Three-dimensional organoid culture models have become important instruments to use for biomarker analysis and drug sensitivity screening. Despite this strong rationale and potential, there is a lack of representative preclinical models from African American patients with lung cancer. Furthermore, there are no studies evaluating the ability to create organoids successfully using samples from different races. As such, our goal was to establish a diverse biobank of organoid models and determine the rate of successful development based on race and other factors. Methods: Patients with lung cancer from a large urban medical center were recruited to participate in the study from 2021 to 2024. Specimens were collected from surgical pulmonary resection or endobronchial biopsy. Each tissue specimen was divided into 3 pieces and allocated for genomic, transcriptomic and organoid development. Once collected, specimens allocated for organoid development were processed within 8 hours. Cells were isolated from tissues by mechanical and enzymatic dissociation and plated in Matrigel drops overlayed with optimized organoid media. Patient demographics, tumor characteristics and method of specimen collection were recorded. Results: A total of 29 patients consented to the study and had evaluable specimens collected. Mean age was 67 years. Fifty-five percent of patients (16/29) were female. White patients were 55 percent of cohort (16/29), while Black patients made up 45% (13/29). Approximately 62 (18/29) percent of patients were diagnosed with adenocarcinoma, followed by squamous cell carcinoma in 28 percent (8/29) of patients. Tumor stage was 55%, 28%, 3% and 14% for stages I, II, III and IV respectively. Overall, there was a successful organoid development rate of 69 percent (20/29). There was a strong trend toward higher success rates in Black patients compared to White patients (85% vs. 56%, p = 0.10). There were no significant differences in successful organoid development based on gender (p = 0.43), histology (p = 0.18) or tumor stage (p = 0.84). Conclusions: Establishment of a racially diverse set of organoid models will be an invaluable tool for biomarker discovery and for screening novel therapeutic agents. Black patients appear to have similar to improved propensity for successful organoid development. Future efforts should be focused on creating diverse biobanks to strengthen precision oncology efforts for Black patients, collectively helping to reduce racial outcomes disparities in patients with lung cancer. Citation Format: Amanda Pilling, Hollis Hutchings, Avi Cohen, Shirish Gadgeel, Ikenna Okereke. Diversifying translational research models to address outcomes disparities in lung cancer [abstract]. In: Proceedings of the 17th AACR Conference on the Science of Cancer Health Disparities in Racial/Ethnic Minorities and the Medically Underserved; 2024 Sep 21-24; Los Angeles, CA. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2024;33(9 Suppl):Abstract nr C172.

A randomized phase II trial on the addition of dutasteride to combined androgen blockade therapy versus combined androgen blockade therapy alone in patients with advanced or metastatic salivary duct carcinoma – the DUCT study protocol

BackgroundSalivary duct carcinoma (SDC) is a rare and aggressive subtype of salivary gland cancer, frequently associated with incurable recurrences and distant metastases (R/M). Proliferation of SDC relies on androgen receptor (AR) signalling, prompting the use of combined androgen blockade (CAB, i.e., luteinizing hormone-releasing hormone agonist and/or AR antagonists) to R/M SDC patients. However, only a subset of patients benefits from such treatments. We have shown that response to CAB is associated with steroid 5α-reductase 1 (SRD5A1) mRNA expression. SRD5A1 catalyses the intracellular conversion of testosterone into the more potent AR-agonist dihydrotestosterone. This conversion can be inhibited by dutasteride, a potent SRD5A1-inhibitor, which is currently prescribed for benign prostatic hyperplasia. We hypothesize that repurposing dutasteride to target AR signalling in SDC could enhance therapeutic response and clinical outcome in SDC patients.MethodsThis prospective, open-label, randomized controlled phase II clinical trial, is designed to investigate whether dutasteride as an adjunct drug to CAB improves response rate and clinical outcome in patients with AR-positive R/M SDC. Patients are divided in two cohorts based on their prior systemic treatments. In cohort A, CAB-naïve patients (n = 74) will be randomly assigned to either a control arm (Arm 1) receiving CAB (goserelin 10.8 mg/3m and bicalutamide 50 mg/OD) or an experimental arm (Arm 2) where dutasteride (0.5 mg/OD) is added to the CAB regimen. In cohort B, patients with disease progression after adjuvant or first-line palliative CAB therapy (max. n = 24) will receive goserelin, bicalutamide, and dutasteride to assess whether the addition of dutasteride can overcome therapy resistance. The primary endpoints are the objective response rate and duration of response. Secondary endpoints are progression-free survival, overall survival, clinical benefit rate, quality of life, and safety. Translational research will be performed to explore molecular target expression differences and their correlation with clinical outcome.DiscussionThe DUCT study addresses an unmet medical need by investigating the repurposing of dutasteride to enhance treatment response and improve clinical outcome for patients with R/M SDC, especially those with limited alternative treatment options, such as HER2-negative cases. By repurposing a registered low-cost drug, this trial’s findings could be readily applied into clinical practice.Trial registrationClinicaltrials.gov Identifier: NCT05513365. Date of registration: August 24, 2022.Protocol versionCurrent protocol version 4.0, February 21, 2024.

Developing Evidence to Support Policy: Protocol for the StrAtegic PoLicy EvIdence-Based Evaluation CeNTer (SALIENT)

Background All federal agencies are required to support appropriation requests with evidence and evaluation (US Public Law 115-435; the Evidence Act). The StrAtegic PoLicy EvIdence-Based Evaluation CeNTer (SALIENT) is 1 of 6 centers that help the Department of Veterans Affairs (VA) meet this requirement. Objective Working with the existing VA evaluation structure, SALIENT evaluations will contribute to (1) optimize policies and programs for veteran populations; (2) improve outcomes regarding health, equity, cost, and provider well-being; (3) advance the science of dissemination and knowledge translation; and (4) expand the implementation and dissemination science workforce. Methods We leverage the Lean Sprint methodology (iterative, incremental, rule-governed approach to clearly defined, and time-boxed work) and 3 cores to develop our evaluation plans collaboratively with operational partners and key stakeholders including veterans, policy experts, and clinicians. The Operations Core will work with evaluation teams to develop timelines, facilitate work, monitor progress, and guide quality improvement within SALIENT. The Methods Core will work with evaluation teams to identify the most appropriate qualitative, quantitative, and mixed methods approaches to address each evaluation, ensure that the analyses are conducted appropriately, and troubleshoot when problems with data acquisition and analysis arise. The Knowledge Translation (KT) Core will target key partners and decision makers using a needs-based market segmentation approach to ensure that needs are incorporated in the dissemination of knowledge. The KT Core will create communications briefs, playbooks, and other materials targeted at these market segments to facilitate implementation of evidence-based practices and maximize the impact of evaluation results. Results The SALIENT team has developed a center infrastructure to support high-priority evaluations, often to be responsive to shifting operational needs and priorities. Our team has engaged in our core missions and operations to rapidly evaluate a high-priority areas, develop a comprehensive Lean Sprint systems redesign approach to training, and accelerate rapid knowledge translation. Conclusions With an array of interdisciplinary expertise, operational partnerships, and integrated resources, SALIENT has an established and evolving infrastructure to rapidly develop and implement high-impact evaluations. Projects are developed with sustained efficiency approaches that can pivot to new priorities as needed and effectively translate knowledge for key stakeholders and policy makers, while creating a learning health system infrastructure to foster the next generation of evaluation and implementation scientists. International Registered Report Identifier (IRRID) PRR1-10.2196/59830

Przyroda w perspektywie kulturoznawczej jako obszar badań

Issues related to the environment, its protection, climate change, etc., has been increasingly entering the field of humanities and social sciences. The article examines the theoretical framework for building a research program for cultural studies for environment, a subfield of cultural sciences relating to issues of nature. The context of consideration oscillates around the development of economic-cultural, and cultural-political issues with themes related to nature and its protection. The text indicates that culturally operationalized knowledge of nature can have both research and implementation translations, becoming the basis for building strategies or theoretical foundations for reflection in the fields of conservation practices.

Charting the Ethical Frontier in Newborn Screening Research: Insights from the NBSTRN ELSI Researcher Needs Survey

From 2008 to 2024, the Newborn Screening Translational Research Network (NBSTRN), part of the National Institute of Child Health and Human Development (NICHD) Hunter Kelly Newborn Screening Program, served as a robust infrastructure to facilitate groundbreaking research in newborn screening (NBS), public health, rare disease, and genomics. Over its sixteen years, NBSTRN developed into a significant international network, supporting innovative research on novel technologies to screen, diagnose, treat, manage, and understand the natural history of more than 280 rare diseases. The NBSTRN tools and resources were used by a variety of stakeholders including researchers, clinicians, state NBS programs, parents, families, and policy makers. Resources and expertise for the newborn screening community in ethical, legal, and social issues (ELSI) has been an important area of focus for the NBSTRN and this includes efforts across the NBS system from pilot studies of candidate conditions to public health implementation of screening for new conditions, and the longitudinal follow-up of NBS-identified individuals to inform health outcomes and disease understanding. In 2023, the NBSTRN conducted a survey to explore ELSI issues in NBS research, specifically those encountered by the NBS community. Since NBS research involves collaboration among researchers, state NBS programs, clinicians, and families, the survey was broadly designed and disseminated to engage all key stakeholders. With responses from 88 members of the NBS community, including researchers and state NBS programs, the survey found that individuals rely most on institutional and collegial resources when they encounter ELSI questions. Most survey responses ranked privacy as extremely or very important in NBS research and identified the need for policies that address informed consent in NBS research. The survey results highlight the need for improved collaborative resources and educational programs focused on ELSI for the NBS community. The survey results inform future efforts in ELSI and NBS research in the United States (U.S.) and the rest of the world, including the development of policies and expanded ELSI initiatives and tools that address the needs of all NBS stakeholders.

Challenges and opportunities of translating animal research into human trials in Ethiopia

Background and objectivesAlthough the goal of translational research is to bring biomedical knowledge from the laboratory to clinical trial and therapeutic products for improving health, this goal has not been well achieved as often as desired because of many barriers documented in different countries. Therefore, the aim of this study was to investigate the challenges and opportunities of translating animal research into human trials in Ethiopia.MethodsA descriptive qualitative study, using in-depth interviews, was conducted in which preclinical and clinical trial researchers who have been involved in animal research or clinical trials as principal investigator were involved. Data were analyzed using inductive thematic process.ResultsSix themes were emerged for challenges: lack of financial and human capacity, inadequate infrastructure, operational obstacles and poor research governance, lack of collaboration, lack of reproducibility of results and prolonged ethical and regulatory approval processes. Furthermore, three themes were synthesized for opportunities: growing infrastructure and resources, improved human capacity and better administrative processes and initiatives for collaboration.Conclusion and recommendationsThe study found that the identified characteristics/features are of high importance either to hurdle or enable the practice of translating animal research into human trials. The study suggests that there should be adequate infrastructure and finance, human capacity building, good research governance, improved ethical and regulatory approval process, multidisciplinary collaboration, and incentives and recognition for researchers to overcome the identified challenges and allow translating of animal research into human trials to proceed more efficiently.

Disrupted basolateral amygdala circuits supports negative valence bias in depressive states

Negative bias is an essential characteristic of depressive episodes leading patients to attribute more negative valence to environmental cues. This negative bias affects all levels of information processing including emotional response, attention and memory, leading to the development and maintenance of depressive symptoms. In this context, pleasant stimuli become less attractive and unpleasant ones more aversive, yet the related neural circuits underlying this bias remain largely unknown. By studying a mice model for depression chronically receiving corticosterone (CORT), we showed a negative bias in valence attribution to olfactory stimuli that responds to antidepressant drug. This result paralleled the alterations in odor value assignment we observed in bipolar depressed patients. Given the crucial role of amygdala in valence coding and its strong link with depression, we hypothesized that basolateral amygdala (BLA) circuits alterations might support negative shift associated with depressive states. Contrary to humans, where limits in spatial resolution of imaging tools impair easy amygdala segmentation, recently unravelled specific BLA circuits implicated in negative and positive valence attribution could be studied in mice. Combining CTB and rabies-based tracing with ex vivo measurements of neuronal activity, we demonstrated that negative valence bias is supported by disrupted activity of specific BLA circuits during depressive states. Chronic CORT administration induced decreased recruitment of BLA-to-NAc neurons preferentially involved in positive valence encoding, while increasing recruitment of BLA-to-CeA neurons preferentially involved in negative valence encoding. Importantly, this dysfunction was dampened by chemogenetic hyperactivation of BLA-to-NAc neurons. Moreover, altered BLA activity correlated with durable presynaptic connectivity changes coming from the paraventricular nucleus of the thalamus, recently demonstrated as orchestrating valence assignment in the amygdala. Together, our findings suggest that specific BLA circuits alterations might support negative bias in depressive states and provide new avenues for translational research to understand the mechanisms underlying depression and treatment efficacy.

Non-Invasive In Vivo Bioimaging in Pigs

Imaging technologies are used to observe the morphology and function of various organs in the body and have become indispensable in a multitude of fields, ranging from basic research to clinical medicine. The luminescence technology based on the luciferin–luciferase reaction has been used in many research fields as an imaging technique, enabling quantitative analysis and detection at high sensitivity. Specifically in gene therapy and cell therapy, it has been developed as an in vivo bioimaging technique mainly for small animal models because of its non-invasive and time-sequential analysis. Currently, translational research using this luminescence imaging technology in pigs for clinical applications is ongoing. In this review, we discuss the progress of these technologies and issues for their clinical application, focusing on pigs, by comparing conventional imaging techniques, including fluorescent probes, with luminescence imaging techniques.

Frequency of weight and body composition increases in advanced non-small cell lung cancer patients during first line therapy.

The primary objective of this study was to assess the frequency of body composition increases and their relationships to changes in body weight in two cohorts of real world, treatment-naïve, advanced non-small cell lung cancer (NSCLC) patients. One cohort received the current standard of care (CSOC), which consisted of immunotherapy and newer chemotherapy regimens, and the other cohort was treated with the former standard of care (FSOC), consisting only of older platinum-containing regimens. CSOC (n=106) and FSOC (n=88) cohorts of advanced NSCLC patients were included in this study. Weights were collected at each clinical visit, and body composition analysis from routine chest computed tomography via automated segmentation software assessed at baseline and at 6 and 12weeks. Standard statistical methods were used to calculate relationships between changes in weight and in body composition. The CSOC cohort contained 106 stage IV NSCLC patients treated between 16/12/2014 and 22/10/2020 while the FSOC cohort contained 88 stage III/IV NSCLC patients treated between 16/6/2006 and 18/11/2014. While each cohort exhibited decreases in median weight, body mass index (BMI), mean skeletal muscle index (SMI) and subcutaneous adipose tissue index (SATI) at the 6 and 12week time points, a subset of patients experienced increases in these parameters. Using a threshold of ≥2.5% increase for weight, BMI, SMI, and SATI at the 12week time point, both cohorts showed similar (20.5% and 27.3%) increases in these parameters. With a cut point of ≥5% increase at 12weeks follow-up, 8.0% to 25.0% of the patients gained ≥5% in weight, BMI, SMI and SATI. Comparing these results in each cohort showed no significant differences. Pearson coefficients for weight change related to changes in SMI and SATI at 6 and 12weeks ranged from 0.31 to 0.58 with all P values <0.02. Pearson coefficients for weight change at 12weeks related to changes in VATI and IMATI ranged from 0.26 to 0.47 with all P values <0.05. Comparison of Pearson coefficients for each cohort showed no significant differences. Although decreases in median weight, BMI, SMI and SATI were observed in both cohorts, similar percentage of patients in each cohort experienced increases in these parameters. These findings, plus the positive correlations between longitudinal measurements of weight, muscle mass and adipose tissue, indicate that weight gain in these patients involves increases in both muscle mass and adipose tissue. Upon validation, these findings could have implications for clinical trial design and for translational research in cancer cachexia.

Walter Brendel and the dawn of transplantation research in Germany

Walter Brendel was a physiologist who headed the Institut of Experimental Surgery at the University of Munich (LMU) from 1961 until 1989. His legendary career began with the development of an anti-human lymphocyte globulin (ALG) at his Institute during the late 1960s. The initial successful treatment of a small number of patients culminated in the co-treatment of the first successfully heart-transplanted patient in Capetown, South Africa (successful reversal with ALG of an acute allograft rejection). Walter Brendel was a pioneering personality whose work has laid a wide platform for the promotion of interdisciplinarily conducted innovative research programs in various domains of translational science and medicine. Among the many innovative achievements, the most notable are: discovery of involvement of the alternative pathway of complement activation in hyperacute xenograft rejection; induction of immunological tolerance to horse IgG as a means to prevent anaphylactic reactions during ALG therapy; development and clinical implementation of the extracorporeal shock wave lithotripsy for extracorporeal destruction of renal and ureteral calculi. The legacy of Brendel continues with the foundation of the Walter-Brendel Kolleg für Transplantationsmedizin (i.e., the German Transplant School for Transplantation Medicine), which has been held annually since 1994.

Ovarian Clear Cell Carcinoma: An Endometriosis-Associated Cancer with Therapeutic Challenges.

Ovarian clear cell carcinoma (OCCC) is a histological subtype of epithelial ovarian cancer with distinct pathological features, molecular profiles, and biological functions. OCCC has high incidence rates in East Asia compared to the Western hemisphere and Europe and is associated with endometriosis. With its relative resistance to conventional treatment regimens and the worst stage-adjusted prognosis among ovarian cancer subtypes, there is an urgent need to optimize therapeutic options and to improve patient outcomes. To achieve this goal, better patient stratification strategies are required. These strategies could derive from comprehensive and in-depth multidimensional analysis of tumor heterogeneity. Understanding intertumor heterogeneity could assist us in stratifying OCCC patients based on features that are prognostic or predictive. Recent genomic, epigenomic, and transcriptomic profiling analyses allow us to provide an integrative perspective on the diverse heterogeneity in OCCC that could pave the way for novel translational research and clinical development in the future.

Current challenges for plant biology research in the Global South.

In an attempt to address the large inequities faced by the plant biology communities from the Global South (i.e. countries located around the tropics and the Southern Hemisphere) at international conferences, this Viewpoint is the reflexive thinking arising from the concurrent session titled 'Arabidopsis and its translational research in the Global South' organized at the International Conference of Arabidopsis Research 2023 (ICAR 2023) in Chiba, Japan in June 2023. Here, we highlight the main obstacles plant biology communities in the Global South face in terms of knowledge production, as measured by the unequal production and citation of publications, investigating and advancing local plant genomics and biodiversity, combating disparities in gender and diversity, and current initiatives to break isolation of scientists.

Abstract B080: A porcine model of pancreatic ductal adenocarcinoma for human scale translational cancer research

Abstract Pancreatic ductal adenocarcinoma (PDAC) remains a highly fatal form of cancer, requiring urgent advancements in diagnostic and therapeutic strategies. Although PDAC mouse models have been crucial in advancing our comprehension of the disease, they present some limitations in replicating key human PDAC aspects. In this study, we present the development of the first large animal model of pancreatic cancer via Cre activatable mutations in the endogenous KRAS and TP53 genes 1,2. In order to activate these mutations in the pancreas, two Cre driver pig lines expressing Cre recombinase from PTF1A 3 and PDX1 were created. Crossing both Cre lines with pigs carrying latent KRAS G12D and TP53 R167H alleles produced double (KC) and triple (KPC) genetically modified animals. Pathological analyses revealed the presence of inter- and intralobular fibrosis with multifocal acinar-to-ductal metaplasia (ADM), some low-grade PanINs, dysplasia, inflammation and duct obstruction in most of the KPC pigs between 3 to 6 months of age. Interestingly, the majority of these pigs already exhibited local metastasis in the lymph nodes, suggesting that the metastatic potential is established early in the tumorigenic process. Age-matched KC pigs exhibited mainly ADM with dysplasia. Flow cytometry and RNA expression analyses of the established pancreatic tumour primary cells revealed a pronounced epithelial-to-mesenchymal transition (EMT). Moreover, both bulk tumour samples and primary tumour cells showed high expression of the pancreatic cancer stem cell marker CD44, with differential expression of its isoforms, including the major isoform and variants 6 and 9. In addition, histological and molecular analyses revealed notable similarities between pig and human PDAC, including molecular subtypes, neuronal invasion and loss of acinar identity. These findings highlight the unique advantage of the pig PDAC model, that allows longitudinal and multi-regional tumour sampling in the absence of any therapeutic interventions. This makes it a valuable tool for developing new diagnostic and therapeutic approaches that can greatly improve patient outcomes in the long run.

Funding priorities and health outcomes in Danish medical research

External research funding is an essential component of the infrastructure of modern, academic research. Priorities in funding decisions drive what knowledge is generated, and how scientists’ careers are shaped. For health research, it can ultimately have implications for health outcomes. The aim of this paper is to illustrate how funding information can be used to track priorities in health research, linking them to disease burdens and research outputs. Furthermore, funding concentrations are analysed from both researcher and disease perspectives, to estimate the influence of personal Matthew-effects on the distribution of health research funding. Denmark is used as the case, including funding information from all major public and private research foundations in the period 2004–2016. Grant information is linked to research outputs and disability-adjusted life-years (DALY rates), for 34,160 publications linked to 2630 grants, receiving DKK 4.8 billion in funding. Data show poor correlation between funding priorities, research activity and disease burdens, with several diseases receiving disproportionate amounts of funding. A research opportunity index is calculated to identify diseases with the highest potential for future investments from a burden-centred point of view. Funding is highly concentrated, both on people and on specific diseases. High funding concentrations on researchers can be a driving factor behind the observed funding-to-burden imbalances, and may risk knowledge stagnation through monopolisation of the market place of ideas. Results indicate that funders of clinical and translational research, as well as some types of biomedical research, need to supplement traditional considerations of scientific excellence with measures of societal challenges and relevance.

Artificial Intelligence in Pain Management: Advancing Translational Science in Digital Health Research from Bench to Bedside

Artificial Intelligence (AI) is rapidly transforming the landscape of healthcare, with particularly profound implications in the field of pain management. This chapter delves into the integration of AI-driven tools that revolutionize the way pain is assessed, monitored, and treated. Through the use of predictive modeling, real-time monitoring, and personalized treatment plans, AI significantly enhances the precision, efficiency, and effectiveness of pain management strategies. The discussion extends to various AI applications, shedding light on the ethical considerations that accompany these technological advancements, as well as outlining future research directions. Collectively, these insights underscore the immense potential of AI to not only improve pain management practices but also to significantly elevate patient outcomes. Central to this transformation is the role of translational science in bridging the gap between theoretical AI models and their practical, clinical applications. This "bench to bedside" approach ensures that innovations in AI are not merely confined to research environments but are actively integrated into real-world patient care. For instance, AI-powered predictive analytics in pain management, driven by sophisticated machine learning algorithms, have progressed from computational experiments to clinical trials, and ultimately, to widespread implementation in healthcare settings. These AI models are now being utilized in hospitals to assess patient pain levels in real-time, predict opioid requirements, and optimize pain management protocols. This progression exemplifies how translational science is facilitating a paradigm shift in healthcare, positioning AI as an indispensable tool in modern pain management.

Pharmacologic Therapy for Spinal Cord Injury.

Neuroprotective strategies aimed at preventing secondary neurologic injury following acute spinal cord injury remain an important area of clinical, translational, and basic science research. Despite recent advancement in the understanding of basic mechanisms of primary and secondary neurologic injury, few pharmacologic agents have shown consistent promise in improving neurologic outcomes following SCI in large randomized clinical trials. The authors review the existing literature and clinical guidelines for pharmacologic therapy investigated for managing acute SCI, including corticosteroids, GM-1 ganglioside (Sygen), Riluzole, opioid antagonists, Cethrin, minocycline, and vasopressors for mean arterial pressure augmentation. Therapies for managing secondary effects of SCI, such as bradycardia, are discussed. Current clinical trials for pharmacotherapy and cellular transplantation following acute SCI are also reviewed. Despite the paucity of current evidence for clinically beneficial post-SCI pharmacotherapy, future research efforts will hopefully elucidate promising therapeutic agents to improve neurologic function.

A gender perspective on diet, microbiome, and sex hormone interplay in cardiovascular disease.

A unique interplay between body and environment embeds and reflects host-microbiome interactions that contribute to sex-differential disease susceptibility, symptomatology, and treatment outcomes. These differences derive from individual biological factors, such as sex hormone action, sex-divergent immune processes, X-linked gene dosage effects, and epigenetics, as well as from their interaction across the lifespan. The gut microbiome is increasingly recognized as a moderator of several body systems that are thus impacted by its function and composition. In humans, biological sex components further interact with gender-specific exposures such as dietary preferences, stressors, and life experiences to form a complex whole, requiring innovative methodologies to disentangle. Here, we summarize current knowledge of the interactions among sex hormones, gut microbiota, immune system, and vascular health and their relevance for sex-differential epidemiology of cardiovascular diseases. We outline clinical implications, identify knowledge gaps, and place emphasis on required future studies to address these gaps. In addition, we provide an overview of the caveats associated with conducting cardiovascular research that require consideration of sex/gender differences. While previous work has inspected several of these components separately, here we call attention to further translational utility of a combined perspective from cardiovascular translational research, gender medicine, and microbiome systems biology.

Thrombospondins: Conserved mediators and modulators of metazoan extracellular matrix.

This review provides a personal overview of significant scientific developments in the thrombospondin field during the course of my career. Thrombospondins are multidomain, multimeric, calcium-binding extracellular glycoproteins with context-specific roles in tissue organisation. They act at cell surfaces and within ECM to regulate cell phenotype and signalling, differentiation and assembly of collagenous ECM, along with tissue-specific roles in cartilage, angiogenesis and synaptic function. More recently, intracellular, homeostatic roles have also been identified. Resolution of structures for the major domains of mammalian thrombospondins has facilitated major advances in understanding thrombospondin biology from molecule to tissue; for example, in illuminating molecular consequences of disease-causing coding mutations in human pseudoachrondroplasia. Although principally studied in vertebrates, thrombospondins are amongst the most ancient of animal ECM proteins, with many invertebrates encoding a single thrombospondin and the thrombospondin gene family of vertebrates originating through gene duplications. Moreover, thrombospondins form one branch of a thrombospondin superfamily that debuted at the origin of metazoans. The super-family includes additional sub-groups, present only in invertebrates, that differ in N-terminal domain organisation, share the distinctive TSP C-terminal region domain architecture and, to the limited extent studied to date, apparently contribute to tissue development and organisation. Finally, major lines of translational research are discussed, related to fibrosis; TSP1, TSP2 and inhibition of angiogenesis; and the alleviation of chronic cartilage tissue pathologies in pseudoachrondroplasia.

EXPRESS: Translational Science and Related Disciplines.

Translational research moves scientific discoveries and innovations across the development spectrum for a particular target or disease, trying to bridge in a multidisciplinary fashion the gap between laboratory scientific discoveries and practical, real-world applications in medicine and in healthcare. Translational research aims to move research findings across settings, specific languages, methodologies and study designs, from laboratory to clinical practice and ultimately into community and population-level health benefits.In contrast, translational science is a distinct field, which evolved over time towards a systematic study and practice of operationalizing the translation of content from one language, ecosystem, environment, contextual landscape, culture, discipline, area or domain into another. It involves systematic and transdisciplinary integration of knowledge from basic science, clinical research and population science to improve human health, better longevity and to ensure disease and disability free lives. Translational science often uses knowledge, operational frameworks and specific capabilities borrowed from other specialties, disciplines and fields such as operations management, implementation and dissemination science, quality improvement and management, project management, public health, intervention science, change management and leadership, decision science, design thinking, functional design, data science, communication and marketing science, etc.The main goal of this article is to open a series of thematic reviews in this journal, introducing the reader to the main definitions, contingencies, touchpoints and overlapping areas between translational science and these related specialties, disciplines and fields of study. Transdisciplinary capabilities borrowing from these related specialties can create a robust translational science machinery for health systems, research organizations and innovation hubs.

Chimeric antigen receptor T-cell therapy for haematological malignancies: Insights from fundamental and translational research to bedside practice.

Autologous chimeric antigen receptor (CAR) T-cell therapy has revolutionized the treatment of lymphoid malignancies, leading to the approval of CD19-CAR T cells for B-cell lymphomas and acute leukaemia, and more recently, B-cell maturation antigen-CAR T cells for multiple myeloma. The long-term follow-up of patients treated in the early clinical trials demonstrates the possibility for long-term remission, suggesting a cure. This is associated with a low incidence of significant long-term side effects and a rapid improvement in the quality of life for responders. In contrast, other types of immunotherapies require prolonged treatments or carry the risk of long-term side effects impairing the quality of life. Despite impressive results, some patients still experience treatment failure or ultimately relapse, underscoring the imperative to improve CAR T-cell therapies and gain a better understanding of their determinants of efficacy to maximize positive outcomes. While the next-generation of CAR T cells will undoubtingly be more potent, there are already opportunities for optimization when utilizing the currently available CAR T cells. This review article aims to summarize the current evidence from clinical, translational and fundamental research, providing clinicians with insights to enhance their understanding and use of CAR T cells.