UNLABELLED: In vivo knockdown of connective tissue growth factor (CTGF/CCN2) was recently shown to attenuate the formation of experimental liver fibrosis. The secreted, cysteine-rich growth factor is proposed to adversely modulate the binding of profibrogenic transforming growth factor beta (TGF-beta) and its natural antagonist bone morphogenetic protein (BMP) to their cognate receptors in several cellular systems, but the functionality of CTGF in modulation of the TGF-beta/BMP signaling pathways is still unknown. This study aims at characterizing a potentially differential modulating role of CTGF on TGF-beta- and BMP7-dependent transactivation of reporter gene [Ad-(CAGA)(12)-MLP-luc, Ad-hCTGF-luc, and Ad-(BRE)(2)-luc reporter gene] expression in rat hepatocytes. In this context, emphasis is also placed on the differential roles of Smad2 and Smad3 in the TGF-beta-dependent transactivation of the endogenous CTGF gene and the CTGF gene reporter, as investigated following adenoviral infection of wild-type and dominant negative Smad2/3 or treatment with the specific inhibitor of Smad3 or ALK5-specific (SB-431542) inhibitor. In this analysis, we found (1) a selective transcriptional activation of the CTGF promoter by Smad2 (but not Smad3); (2) the failure of BMP7 to inhibit the transcriptional activation of the Smad3-selective (CAGA)(12)-luc reporter by TGF-beta, as well as the failure of TGF-beta to inhibit the transcriptional activation of the Smad5-selective (BRE)(2)-luc reporter by BMP7; and (3) the sensitization of hepatocytes toward TGF-beta type I receptor (ALK5)/Smad2 and Smad3-mediated TGF-beta signaling by CTGF, whereas BMP type I receptor (ALK1)/Smad5-mediated BMP7 signaling is not modulated. CONCLUSION: CTGF acts as a Smad2-dependent sensitizer of TGF-beta actions that does not influence BMP7 signaling in hepatocytes.

Over the past few years, Advanced Therapy Medicinal Products (ATMPs), especially cell and gene therapies, have brought about a remarkable transformation in the field of therapeutics. ATMPs have the potential to be tailored to individual patients based on their distinct molecular characteristics, making them a crucial aspect of personalized medicine (PM) strategies. Unlocking the full potential of ATMPs is crucial for them to become the treatments of the future. Despite their immense promise, their success is hindered by significant complexity, as evidenced by various systemic bottlenecks in the realms of science, clinical implementation, and regulation. Presently, ATMPs face challenges such as a limited understanding and predictability of in vivo cell fate specific to each patient, regulatory issues caused by rapid technological advancements, inadequate standardization in data acquisition, limited reproducibility during preclinical development, and insufficient knowledge exchange among key stakeholders. Addressing these aspects is essential to fully harness the benefits of ATMPs in healthcare. EATRIS, the European Research Infrastructure for Translational Medicine, is actively enhancing its capabilities in the field of PM through a series of key initiatives. These efforts aim to support also ATMP development and are focused on delivering novel and innovative scientific tools for the scientific community. The final aim is to create the right ecosystem for more effective ATMP development in Europe, by better serving academia and industry in the translation of ATMPs for patient benefit.

Molecular characterization of a biological sample, e.g., with omics approaches, is fundamental for the development and implementation of personalized and precision medicine approaches. In this context, quality assessment is one of the most critical aspects. Accurate performance and interpretation of omics techniques is based on consensus, harmonization, and standardization of protocols, procedures, data analysis and reference values and materials. EATRIS, the European Infrastructure for Translational Medicine (www.EATRIS.eu), brings together resources and services to support researchers in developing their biomedical discoveries into novel translational tools and interventions for better health outcomes. Here we describe the efforts within the Horizon 2020 EATRIS-Plus project and activities of member facilities of EATRIS towards quality assessment of pre-clinical sample processing, clinical omics data generation, multi-omics data integration, and dissemination of the resources in a Multi-Omics Toolbox, which is the principal deliverable of the EATRIS-Plus project for the consolidation of EATRIS towards translational medicine. Supplementary Information: The online version contains supplementary material available at 10.1007/s43657-024-00170-0.

Beyond the algorithm: why oncology nursing in Asia-Pacific needs evidence-based AI evaluation A nurse working in a busy oncology ward in Manila receives an alert from a newly installed artificial intelligence (AI) clinical decision support system.The tool recommends adjusting the symptom management plan for a patient undergoing chemotherapy for gastric cancer.The algorithm's confidence score is high.But how does she know whether to trust it?Has this tool been validated on Filipino patients?Has anyone evaluated whether it improves the outcomes she cares about most, patient comfort, timely intervention, safe care transitions?These are not hypothetical questions.They represent the daily reality confronting oncology nurses across the Asia-Pacific as AI tools proliferate in cancer care settings.We argue that the rapid adoption of AI in oncology across the Asia-Pacific region has dramatically outpaced the evidence base required to guide its responsible use.Oncology nurses must demand and lead rigorous, context-sensitive evaluation of these tools.Moving beyond technical accuracy to determine whether AI improves cancer care in diverse clinical environments of our region.Achieving this goal requires methodological innovation, drawing upon pragmatic trials, hybrid designs, real-world evidence (RWE), and health technology assessment (HTA) frameworks that can accommodate the unique characteristics of AI-based health interventions.

UNLABELLED: Liver fibrosis is a major cause of morbidity and mortality worldwide. Platelets are involved in liver damage, but the underlying molecular mechanisms remain elusive. Here, we investigate the platelet-derived chemokine (C-X-C motif) ligand 4 (CXCL4) as a molecular mediator of fibrotic liver damage. Serum concentrations and intrahepatic messenger RNA of CXCL4 were measured in patients with chronic liver diseases and mice after toxic liver injury. Platelet aggregation in early fibrosis was determined by electron microscopy in patients and by immunohistochemistry in mice. Cxcl4(-/-) and wild-type mice were subjected to two models of chronic liver injury (CCl(4) and thioacetamide). The fibrotic phenotype was analyzed by histological, biochemical, and molecular analyses. Intrahepatic infiltration of immune cells was investigated by fluorescence-activated cell sorting, and stellate cells were stimulated with recombinant Cxcl4 in vitro. The results showed that patients with advanced hepatitis C virus-induced fibrosis or nonalcoholic steatohepatitis had increased serum levels and intrahepatic CXCL4 messenger RNA concentrations. Platelets were found directly adjacent to collagen fibrils. The CCl(4) and thioacetamide treatment led to an increase of hepatic Cxcl4 levels, platelet activation, and aggregation in early fibrosis in mice. Accordingly, genetic deletion of Cxcl4 in mice significantly reduced histological and biochemical liver damage in vivo, which was accompanied by changes in the expression of fibrosis-related genes (Timp-1 [tissue inhibitor of matrix metalloproteinase 1], Mmp9 [matrix metalloproteinase 9], Tgf-beta [transforming growth factor beta], IL10 [interleukin 10]). Functionally, Cxcl4(-/-) mice showed a strongly decreased infiltration of neutrophils (Ly6G) and CD8(+) T cells into the liver. In vitro, recombinant murine Cxcl4 stimulated the proliferation, chemotaxis, and chemokine expression of hepatic stellate cells. CONCLUSION: The results underscore an important role of platelets in chronic liver damage and imply a new target for antifibrotic therapies.

UNLABELLED: Interleukin-27 (IL-27) is a cytokine belonging to the IL-6/IL-12 cytokine family. It is secreted by antigen-presenting cells, strongly acts on T cells, and also stimulates innate immune cells. In most studies, the effects of IL-27 on T cells were investigated; however, not much is known about possible effects of IL-27 on other cell types. IL-27 signals via the common IL-6-type cytokine receptor chain gp130 and the IL-27-specific chain WSX-1. Given the importance of gp130 in regulating liver responses such as the acute phase response or liver regeneration, we investigated whether IL-27 could also have a function in liver cells. We find that IL-27 stimulates hepatoma cells and hepatocytes by inducing a sustained signal transducer and activator of transcription (STAT)1 and STAT3 activation. Whereas the STAT3 mediated responses to IL-27 (gamma-fibrinogen and hepcidin induction) are not detectable, we observe an interferon-gamma (IFN-gamma)-like STAT1 response leading to the induction of interferon-regulated proteins such as STAT1, STAT2, interferon response factor (IRF)-1, IRF-9, myxovirus resistance A and guanylate binding protein 2. CONCLUSION: Our study provides evidence for a function of IL-27 in hepatoma cells and hepatocytes and shows that IL-27 responses are not restricted to the classical immune cells. Our results suggest that IL-27 exerts IFN-like functions in liver cells and that it can contribute to the antiviral response in these cells.

BACKGROUND: Personalised medicine is a medical model that aims to provide tailor-made prevention and treatment strategies for defined groups of individuals. The concept brings new challenges to the translational step, both in clinical relevance and validity of models. We have developed a set of recommendations aimed at improving the robustness of preclinical methods in translational research for personalised medicine. METHODS: These recommendations have been developed following four main steps: (1) a scoping review of the literature with a gap analysis, (2) working sessions with a wide range of experts in the field, (3) a consensus workshop, and (4) preparation of the final set of recommendations. RESULTS: Despite the progress in developing innovative and complex preclinical model systems, to date there are fundamental deficits in translational methods that prevent the further development of personalised medicine. The literature review highlighted five main gaps, relating to the relevance of experimental models, quality assessment practices, reporting, regulation, and a gap between preclinical and clinical research. We identified five points of focus for the recommendations, based on the consensus reached during the consultation meetings: (1) clinically relevant translational research, (2) robust model development, (3) transparency and education, (4) revised regulation, and (5) interaction with clinical research and patient engagement. Here, we present a set of 15 recommendations aimed at improving the robustness of preclinical methods in translational research for personalised medicine. CONCLUSIONS: Appropriate preclinical models should be an integral contributor to interventional clinical trial success rates, and predictive translational models are a fundamental requirement to realise the dream of personalised medicine. The implementation of these guidelines is ambitious, and it is only through the active involvement of all relevant stakeholders in this field that we will be able to make an impact and effectuate a change which will facilitate improved translation of personalised medicine in the future.

Nonalcoholic fatty liver disease (NAFLD) is a burgeoning health problem of unknown etiology that varies in prevalence among ancestry groups. To identify genetic variants contributing to differences in hepatic fat content, we carried out a genome-wide association scan of nonsynonymous sequence variations (n = 9,229) in a population comprising Hispanic, African American and European American individuals. An allele in PNPLA3 (rs738409[G], encoding I148M) was strongly associated with increased hepatic fat levels (P = 5.9 × 10(-10)) and with hepatic inflammation (P = 3.7 × 10(-4)). The allele was most common in Hispanics, the group most susceptible to NAFLD; hepatic fat content was more than twofold higher in PNPLA3 rs738409[G] homozygotes than in noncarriers. Resequencing revealed another allele of PNPLA3 (rs6006460[T], encoding S453I) that was associated with lower hepatic fat content in African Americans, the group at lowest risk of NAFLD. Thus, variation in PNPLA3 contributes to ancestry-related and inter-individual differences in hepatic fat content and susceptibility to NAFLD.

Background Burnout negatively impacts healthcare professionals’ well-being, leading to an increased risk of human errors and patient harm. There are limited assessments of burnout and associated stressors among acute care and trauma surgery teams. Methods Acute care and trauma surgery team members at a US academic medical center were administered a survey that included a 2-item Maslach Burnout Inventory and 21 workplace stressors based on the National Academy of Medicine’s systems model of clinician burnout and professional well-being. Stressors were summarized and presented to participants in focus groups. Contextual inquiries (CIs) were conducted to gather additional information about key stressors. Qualitative data were used to generate an affinity model, which participants then validated and used to prioritize top stressors. Participants rated stressors by level of impact and level of effort, and improvement recommendations were made based on these results. Results 74% (n=14/19) acute care and trauma surgery team members reported high burnout. Key stressors included inadequate staffing, organizational culture, excessive workload, and inefficient workflows. Attending faculty (surgeons) classified the following key priorities for improvement: (i) improve throughput and patient flow, (ii) provide better information technology support, and (iii) improve rewards and support. Non-faculty (advanced practice providers (APPs), nurses, staff) classified the following for improvement: (i) align APP job responsibilities, (ii) improve lack of recognition from leadership, and (iii) robust and consistent APP training. Conclusions A contextual design approach to studying burnout using surveys, focus groups, CIs, modeling, and validation and prioritization is a feasible method for identifying key stressors and improvements that may enable more impactful and appropriately targeted interventions. Results indicate high levels of burnout among acute care and trauma surgery team members, requiring prioritized attention to operational and relationship issues necessary to care for patients. Efforts to improve surgery teams’ workflows, auxiliary support, compensation, and relationships with leadership may address burnout. Level of evidence Level V.

Introduction: Post-operative atrial fibrillation (POAF) is one of the most common complications after cardiac surgery. The role of atrial structural and molecular remodeling prior to surgery in its pathogenesis is still unknown. Hypothesis: The aim of this study was to identify right atrial histopathological abnormalities at the time of cardiac surgery that might predict the development of POAF. Methods: The right atrial appendage was biopsied in 89 patients included in the international clinical trial OPERA (Omega-3 Fatty Acids for Prevention of Post-Operative Atrial Fibrillation) undergoing cardiac surgery. After fixation in formalin and embedding in paraffin, myocardial biopsies were cut into 4-μm histological sections which were stained with Periodic-Acid Shiff (to evaluate cardiomyocyte diameter, myocytolysis and pathologic glycogen accumulation) or Masson trichrome (to quantify interstitial fibrosis). Further sections were immunostained for the gap junction protein connexin43 (Cx43). Results: Demogr...

B1MG WP1 facilitates the engagement of stakeholders in the field of genomics-based health in the B1MG project and 1+MG initiative. Priority of the overall stakeholder engagement process in B1MG is to involve key stakeholders in the essential workstreams organised as part of the B1MG Work Packages (WPs) and their corresponding 1+MG Working Groups (WGs). Stakeholders are (experts of) organisations of a variable nature and scope, and B1MG chooses to organise their involvement at multiple levels. Stakeholders are here defined as European/international, national and regional organisations and individuals active in and/or interested in the development and implementation of genomics-based health in national and regional healthcare systems. In particular, B1MG addresses stakeholders that have the expertise and capacities to play a role in the European 1+MG Initiative and are committed to realising the key goal of the 1+MG initiative: the ability to make genomics and related health data accessible across borders for trans-national use in research, diagnostics and/or innovation of healthcare. The B1MG stakeholder organisation arranges for a general Stakeholder Forum, bringing together all stakeholders engaged in, or interested in the 1+MG initiative. Stakeholder Forum meetings are held once per year, co-organised with leads/teams of all B1MG WPs/1+MG WGs to discuss the progress in the project and 1+MG initiative. The WP1 team will co-organise, facilitate and report on the outcome of these yearly meetings in yearly reports. Through a dedicated Stakeholder Portal arranged through WP1 in close collaboration with WP6 (technical implementation), B1MG arranges for a central communication channel with stakeholders on matters dealt with in the B1MG operational work packages. Experts of stakeholder organisations are invited to register to allow access to the portal, granted upon WP1 approval. All WPs of the B1MG project use the portal to inform and consult stakeholders in the design of scoping papers, recommendations, guidelines and other output. B1MG facilitates the participation of (experts of) selected stakeholders in workstreams organised in the B1MG project WPs and corresponding WGs of the 1+MG initiative. In addition, a limited selection of specific stakeholder Partner Projects is engaged. These projects have important capacity and ongoing work that fully aligns with the 1+MG/B1MG ambitions. Only projects that can actively contribute to the workstreams organised in the 1+MG initiative and are committed to help realise the 1+MG goals can become B1MG Partner Projects. Stakeholders are also involved in addressing the overarching subject of citizen trust and public engagement, crucial for the implementation of genomics-based health strategies across Europe. B1MG WP1 facilitates the B1MG process to establish recommendations to realise citizen engagement and build citizen trust across 1+MG.

ABSTRACT Molecular characterization of a biological sample, e.g., with omics approaches, is fundamental for the development and implementation of personalized and precision medicine approaches. In this context, quality assessment is one of the most critical aspects. Accurate performance and interpretation of omics techniques is based on consensus, harmonization, and standardization of protocols, procedures, data analysis and reference values and materials. EATRIS, the European Infrastructure for Translational Medicine ( www.EATRIS.eu ), brings together resources and services to support researchers in developing their biomedical discoveries into novel translational tools and interventions for better health outcomes. Here we describe activities of member facilities of EATRIS towards quality assessment of pre-clinical sample processing, clinical omics data generation, multi-omics data integration, and dissemination of the resources in a Multi-Omics Toolbox, the principal deliverable of the EATRIS Plus project for the consolidation of EATRIS towards translational Medicine.