The prognostic value of JUNB-positive CTCs in metastatic breast cancer: from bioinformatics to phenotypic characterization.

BACKGROUND: Circulating tumor cells (CTCs) are important for metastatic dissemination of cancer. They can provide useful information, regarding biological features and tumor heterogeneity; however, their detection and characterization are difficult due to their limited number in the bloodstream and their mesenchymal characteristics. Therefore, new biomarkers are needed to address these questions. METHODS: Bioinformatics functional enrichment analysis revealed a subgroup of 24 genes, potentially overexpressed in CTCs. Among these genes, the chemokine receptor CXCR4 plays a central role. After prioritization according to the CXCR4 corresponding pathways, five molecules (JUNB, YWHAB, TYROBP, NFYA, and PRDX1) were selected for further analysis in biological samples. The SKBR3, MDA-MB231, and MCF7 cell lines, as well as PBMCs from normal (n = 10) blood donors, were used as controls to define the expression pattern of all the examined molecules. Consequently, 100 previously untreated metastatic breast cancer (mBC) patients (n = 100) were analyzed using the following combinations of antibodies: CK (cytokeratin)/CXCR4/JUNB, CK/NFYA/ΥWHΑΒ (14-3-3), and CK/TYROBP/PRDX1. A threshold value for every molecule was considered the mean expression in normal PBMCs. RESULTS: Quantification of CXCR4 revealed overexpression of the receptor in SKBR3 and in CTCs, following the subsequent scale (SKBR3>CTCs>Hela>MCF7>MDA-MB231). JUNB was also overexpressed in CTCs (SKBR3>CTCs>MCF7>MDA-MB231>Hela). According to the defined threshold for each molecule, CXCR4-positive CTCs were identified in 90% of the patients with detectable tumor cells in their blood. In addition, 65%, 75%, 14.3%, and 12.5% of the patients harbored JUNB-, TYROBP-, NFYA-, and PRDX-positive CTCs, respectively. Conversely, none of the patients revealed YWHAB-positive CTCs. Interestingly, JUNB expression in CTCs was phenotypically and statistically enhanced compared to patients' blood cells (p = 0.002) providing a possible new biomarker for CTCs. Furthermore, the detection of JUNB-positive CTCs in patients was associated with poorer PFS (p = 0.015) and OS (p = 0.002). Moreover, JUNB staining of 11 primary and 4 metastatic tumors from the same cohort of patients revealed a dramatic increase of JUNB expression in metastasis. CONCLUSIONS: CXCR4, JUNB, and TYROBP were overexpressed in CTCs, but only the expression of JUNB was associated with poor prognosis, providing a new biomarker and a potential therapeutic target for the elimination of CTCs.

PharmActa: Personalized pharmaceutical care eHealth platform for patients and pharmacists.

Community pharmacists are critically placed in the patient care chain being an extended frontline within primary healthcare networks across Europe. They are trained to ensure safe and effective medication use, a crucial and responsible role, extending beyond the common misconception limited to just providing timely access to medicines for the population. Technology-wise, eHealth being committed to an effective, networked, patient-centered and accessible healthcare would prove a real asset in this direction by achieving improved therapy adherence with better outcomes and direct contribution to a cost-effective healthcare system. In this work, we present PharmActa, a personalized eHealth platform that addresses key features of pharmaceutical care and enhances communication of pharmacists with patients for optimizing pharmacotherapy. PharmActa empowers patients by providing pharmaceutical care services, such as drug interactions tools, reminders for assisting adhesion and compliance, information regarding adverse drug reactions, as well as pharmacovigilance along with related tools for healthcare management. In addition, it allows the pharmacists to review the medication history in order to provide personalized pharmaceutical care services; thus enhancing their role as healthcare providers. Finally, a mechanism allowing such a system to be interconnected with a developed medical repository following European and International interoperability standards, is also presented. Thus far, the evaluation results presented in this work indicate that PharmActa can be of great benefit to healthcare professionals, especially pharmacists and patients.

Semantic biomedical resource discovery: a Natural Language Processing framework.

BACKGROUND: A plethora of publicly available biomedical resources do currently exist and are constantly increasing at a fast rate. In parallel, specialized repositories are been developed, indexing numerous clinical and biomedical tools. The main drawback of such repositories is the difficulty in locating appropriate resources for a clinical or biomedical decision task, especially for non-Information Technology expert users. In parallel, although NLP research in the clinical domain has been active since the 1960s, progress in the development of NLP applications has been slow and lags behind progress in the general NLP domain. The aim of the present study is to investigate the use of semantics for biomedical resources annotation with domain specific ontologies and exploit Natural Language Processing methods in empowering the non-Information Technology expert users to efficiently search for biomedical resources using natural language. METHODS: A Natural Language Processing engine which can "translate" free text into targeted queries, automatically transforming a clinical research question into a request description that contains only terms of ontologies, has been implemented. The implementation is based on information extraction techniques for text in natural language, guided by integrated ontologies. Furthermore, knowledge from robust text mining methods has been incorporated to map descriptions into suitable domain ontologies in order to ensure that the biomedical resources descriptions are domain oriented and enhance the accuracy of services discovery. The framework is freely available as a web application at ( http://calchas.ics.forth.gr/ ). RESULTS: For our experiments, a range of clinical questions were established based on descriptions of clinical trials from the ClinicalTrials.gov registry as well as recommendations from clinicians. Domain experts manually identified the available tools in a tools repository which are suitable for addressing the clinical questions at hand, either individually or as a set of tools forming a computational pipeline. The results were compared with those obtained from an automated discovery of candidate biomedical tools. For the evaluation of the results, precision and recall measurements were used. Our results indicate that the proposed framework has a high precision and low recall, implying that the system returns essentially more relevant results than irrelevant. CONCLUSIONS: There are adequate biomedical ontologies already available, sufficiency of existing NLP tools and quality of biomedical annotation systems for the implementation of a biomedical resources discovery framework, based on the semantic annotation of resources and the use on NLP techniques. The results of the present study demonstrate the clinical utility of the application of the proposed framework which aims to bridge the gap between clinical question in natural language and efficient dynamic biomedical resources discovery.

Synergies of Radiomics and Transcriptomics in Lung Cancer Diagnosis: A Pilot Study.

Radiotranscriptomics is an emerging field that aims to investigate the relationships between the radiomic features extracted from medical images and gene expression profiles that contribute in the diagnosis, treatment planning, and prognosis of cancer. This study proposes a methodological framework for the investigation of these associations with application on non-small-cell lung cancer (NSCLC). Six publicly available NSCLC datasets with transcriptomics data were used to derive and validate a transcriptomic signature for its ability to differentiate between cancer and non-malignant lung tissue. A publicly available dataset of 24 NSCLC-diagnosed patients, with both transcriptomic and imaging data, was used for the joint radiotranscriptomic analysis. For each patient, 749 Computed Tomography (CT) radiomic features were extracted and the corresponding transcriptomics data were provided through DNA microarrays. The radiomic features were clustered using the iterative K-means algorithm resulting in 77 homogeneous clusters, represented by meta-radiomic features. The most significant differentially expressed genes (DEGs) were selected by performing Significance Analysis of Microarrays (SAM) and 2-fold change. The interactions among the CT imaging features and the selected DEGs were investigated using SAM and a Spearman rank correlation test with a False Discovery Rate (FDR) of 5%, leading to the extraction of 73 DEGs significantly correlated with radiomic features. These genes were used to produce predictive models of the meta-radiomics features, defined as p-metaomics features, by performing Lasso regression. Of the 77 meta-radiomic features, 51 can be modeled in terms of the transcriptomic signature. These significant radiotranscriptomics relationships form a reliable basis to biologically justify the radiomics features extracted from anatomic imaging modalities. Thus, the biological value of these radiomic features was justified via enrichment analysis on their transcriptomics-based regression models, revealing closely associated biological processes and pathways. Overall, the proposed methodological framework provides joint radiotranscriptomics markers and models to support the connection and complementarities between the transcriptome and the phenotype in cancer, as demonstrated in the case of NSCLC.

MI-Common Data Model: Extending Observational Medical Outcomes Partnership-Common Data Model (OMOP-CDM) for Registering Medical Imaging Metadata and Subsequent Curation Processes.

PURPOSE: The explosion of big data and artificial intelligence has rapidly increased the need for integrated, homogenized, and harmonized health data. Many common data models (CDMs) and standard vocabularies have appeared in an attempt to offer harmonized access to the available information, with Observational Medical Outcomes Partnership (OMOP)-CDM being one of the most prominent ones, allowing the standardization and harmonization of health care information. However, despite its flexibility, still capturing imaging metadata along with the corresponding clinical data continues to pose a challenge. This challenge arises from the absence of a comprehensive standard representation for image-related information and subsequent image curation processes and their interlinkage with the respective clinical information. Successful resolution of this challenge holds the potential to enable imaging and clinical data to become harmonized, quality-checked, annotated, and ready to be used in conjunction, in the development of artificial intelligence models and other data-dependent use cases. METHODS: To address this challenge, we introduce medical imaging (MI)-CDM-an extension of the OMOP-CDM specifically designed for registering medical imaging data and curation-related processes. Our modeling choices were the result of iterative numerous discussions among clinical and AI experts to enable the integration of imaging and clinical data in the context of the ProCAncer-I project, for answering a set of clinical questions across the prostate cancer's continuum. RESULTS: Our MI-CDM extension has been successfully implemented for the use case of prostate cancer for integrating imaging and curation metadata along with clinical information by using the OMOP-CDM and its oncology extension. CONCLUSION: By using our proposed terminologies and standardized attributes, we demonstrate how diverse imaging modalities can be seamlessly integrated in the future.

Data infrastructures for AI in medical imaging: a report on the experiences of five EU projects.

Artificial intelligence (AI) is transforming the field of medical imaging and has the potential to bring medicine from the era of 'sick-care' to the era of healthcare and prevention. The development of AI requires access to large, complete, and harmonized real-world datasets, representative of the population, and disease diversity. However, to date, efforts are fragmented, based on single-institution, size-limited, and annotation-limited datasets. Available public datasets (e.g., The Cancer Imaging Archive, TCIA, USA) are limited in scope, making model generalizability really difficult. In this direction, five European Union projects are currently working on the development of big data infrastructures that will enable European, ethically and General Data Protection Regulation-compliant, quality-controlled, cancer-related, medical imaging platforms, in which both large-scale data and AI algorithms will coexist. The vision is to create sustainable AI cloud-based platforms for the development, implementation, verification, and validation of trustable, usable, and reliable AI models for addressing specific unmet needs regarding cancer care provision. In this paper, we present an overview of the development efforts highlighting challenges and approaches selected providing valuable feedback to future attempts in the area.Key points• Artificial intelligence models for health imaging require access to large amounts of harmonized imaging data and metadata.• Main infrastructures adopted either collect centrally anonymized data or enable access to pseudonymized distributed data.• Developing a common data model for storing all relevant information is a challenge.• Trust of data providers in data sharing initiatives is essential.• An online European Union meta-tool-repository is a necessity minimizing effort duplication for the various projects in the area.

Data Ingestion for AI in Prostate Cancer.

Prostate cancer (PCa) is one of the most prevalent cancers in the male population. Current clinical practices lead to overdiagnosis and overtreatment necessitating more effective tools for improving diagnosis, thus the quality of life of patients. Recent advances in infrastructure, computing power and artificial intelligence enable the collection of tremendous amounts of clinical and imaging data that could assist towards this end. ProCAncer-I project aims to develop an AI platform integrating imaging data and models and hosting the largest collection of PCa (mp)MRI, anonymized image data worldwide. In this paper, we present an overview of the overall architecture focusing on the data ingestion part of the platform. We describe the workflow followed for uploading the data and the main repositories for storing imaging data, clinical data and their corresponding metadata.

The ACGT Master Ontology and its applications--towards an ontology-driven cancer research and management system.

OBJECTIVE: This paper introduces the objectives, methods and results of ontology development in the EU co-funded project Advancing Clinico-genomic Trials on Cancer-Open Grid Services for Improving Medical Knowledge Discovery (ACGT). While the available data in the life sciences has recently grown both in amount and quality, the full exploitation of it is being hindered by the use of different underlying technologies, coding systems, category schemes and reporting methods on the part of different research groups. The goal of the ACGT project is to contribute to the resolution of these problems by developing an ontology-driven, semantic grid services infrastructure that will enable efficient execution of discovery-driven scientific workflows in the context of multi-centric, post-genomic clinical trials. The focus of the present paper is the ACGT Master Ontology (MO). METHODS: ACGT project researchers undertook a systematic review of existing domain and upper-level ontologies, as well as of existing ontology design software, implementation methods, and end-user interfaces. This included the careful study of best practices, design principles and evaluation methods for ontology design, maintenance, implementation, and versioning, as well as for use on the part of domain experts and clinicians. RESULTS: To date, the results of the ACGT project include (i) the development of a master ontology (the ACGT-MO) based on clearly defined principles of ontology development and evaluation; (ii) the development of a technical infrastructure (the ACGT Platform) that implements the ACGT-MO utilizing independent tools, components and resources that have been developed based on open architectural standards, and which includes an application updating and evolving the ontology efficiently in response to end-user needs; and (iii) the development of an Ontology-based Trial Management Application (ObTiMA) that integrates the ACGT-MO into the design process of clinical trials in order to guarantee automatic semantic integration without the need to perform a separate mapping process.

ACGT: advancing clinico-genomic trials on cancer - four years of experience.

The challenges regarding seamless integration of distributed, heterogeneous and multilevel data arising in the context of contemporary, post-genomic clinical trials cannot be effectively addressed with current methodologies. An urgent need exists to access data in a uniform manner, to share information among different clinical and research centers, and to store data in secure repositories assuring the privacy of patients. Advancing Clinico-Genomic Trials (ACGT) was a European Commission funded Integrated Project that aimed at providing tools and methods to enhance the efficiency of clinical trials in the -omics era. The project, now completed after four years of work, involved the development of both a set of methodological approaches as well as tools and services and its testing in the context of real-world clinico-genomic scenarios. This paper describes the main experiences using the ACGT platform and its tools within one such scenario and highlights the very promising results obtained.

Emerging and Established Trends to Support Secure Health Information Exchange.

This work aims to provide information, guidelines, established practices and standards, and an extensive evaluation on new and promising technologies for the implementation of a secure information sharing platform for health-related data. We focus strictly on the technical aspects and specifically on the sharing of health information, studying innovative techniques for secure information sharing within the health-care domain, and we describe our solution and evaluate the use of blockchain methodologically for integrating within our implementation. To do so, we analyze health information sharing within the concept of the PANACEA project that facilitates the design, implementation, and deployment of a relevant platform. The research presented in this paper provides evidence and argumentation toward advanced and novel implementation strategies for a state-of-the-art information sharing environment; a description of high-level requirements for the transfer of data between different health-care organizations or cross-border; technologies to support the secure interconnectivity and trust between information technology (IT) systems participating in a sharing-data "community"; standards, guidelines, and interoperability specifications for implementing a common understanding and integration in the sharing of clinical information; and the use of cloud computing and prospectively more advanced technologies such as blockchain. The technologies described and the possible implementation approaches are presented in the design of an innovative secure information sharing platform in the health-care domain.

PANACEA resilient and secure toolkit for healthcare infrastructures.

Healthcare organizations are frequently subject to cybersecurity incidents. The outbreak of a pandemic such as COVID-19 has shown the need for specific operational and organizational measures to be in place in order to reduce the risk of successful cyberattacks. Time will be key: preparation is needed to ensure quick secure set-up of additional resources (IT, staff, medical devices) when the next emergency will hit. The PANACEA Solution Toolkit is a suite of complementary tools to provide Health Care Organizations (HCO) with assessment, guidance, technical and organizational "infrastructure" to address the cybersecurity challenges. It provides support for fortifying health organizations against cyber threats on multiple different levels (technical, behavioral, organizational, strategical) and across a diverse set of workflows and scenarios. In order to determine whether the toolkit satisfies the specific business and users' requirements in the selected use cases, a detailed validation plan and execution roadmap is established taking into account the constraints of the current emergent situation.

Scientific discovery workflows in bioinformatics: a scenario for the coupling of molecular regulatory pathways and gene-expression profiles.

Scientific workflow technologies and tools have become an important weapon in the arsenal of the bioinformaticians and computational biologists. To support this view we present a typical exploratory data analysis scenario involving the combination of information from Gene Regulatory Networks and gene expression data. We further describe the implementation of this scenario using the Workflow Environment implemented in the context of a large EU funded project. In this process desirable features that similar environments should offer are identified and analyzed. The ICT platform presented is evaluated using the chosen scenario as a benchmark. Finally we conclude with an outlook to future work.

CXCR4 and JUNB double-positive disseminated tumor cells are detected frequently in breast cancer patients at primary diagnosis.

BACKGROUND: The chemokine receptor CXCR4 and the transcription factor JUNB, expressed on a variety of tumor cells, seem to play an important role in the metastatic process. Since disseminated tumor cells (DTCs) in the bone marrow (BM) have been associated with worse outcomes, we evaluated the expression of CXCR4 and JUNB in DTCs of primary, nonmetastatic breast cancer (BC) patients before the onset of any systemic treatment. METHODS: Bilateral BM (10 ml) aspirations of 39 hormone receptor (HR)-positive, HER2-negative BC patients were assessed for the presence of DTCs using the following combination of antibodies: pan-cytokeratin (A45-B/B3)/CXCR4/JUNB. An expression pattern of the examined proteins was created using confocal laser scanning microscopy, Image J software and BC cell lines. RESULTS: CXCR4 was overexpressed in cancer cells and DTCs, with the following hierarchy of expression: SKBR3 > MCF7 > DTCs > MDA-MB231. Accordingly, the expression pattern of JUNB was: DTCs > MDA-MB231 > SKBR3 > MCF7. The mean intensity of CXCR4 (6411 ± 334) and JUNB (27725.64 ± 470) in DTCs was statistically higher compared with BM hematopoietic cells (2009 ± 456, p = 0.001; and 11112.89 ± 545, p = 0.001, respectively). The (CXCR4+JUNB+CK+) phenotype was the most frequently detected [90% (35/39)], followed by the (CXCR4-JUNB+CK+) phenotype [36% (14/39)]. However, (CXCR4+JUNB-CK+) tumor cells were found in only 5% (3/39) of patients. Those patients harboring DTCs with the (CXCR4+JUNB+CK+) phenotype revealed lower overall survival (Cox regression: p = 0.023). CONCLUSIONS: (CXCR4+JUNB+CK+)-expressing DTCs, detected frequently in the BM of BC patients, seem to identify a subgroup of patients at higher risk for relapse that may be considered for close follow up.

Cyber-attacks and threats for healthcare - a multi-layer thread analysis.

Due to the advent of novel technologies and digital opportunities allowing to simplify user lives, healthcare is increasingly evolving towards digitalization. This represent a great opportunity on one side but it also exposes healthcare organizations to multiple threats (both digital and not) that may lead an attacker to compromise the security of medial processes and potentially patients' safety. Today technical cybersecurity countermeasures are used to protect the confidentiality, integrity and availability of data and information systems - especially in the healthcare domain. This paper will report on the current state of the art about cyber security in the Healthcare domain with particular emphasis on current threats and methodologies to analyze and manage them. In addition, it will introduce a multi-layer attack model providing a new perspective for attack and threat identification and analysis.

Workflows for intelligent monitoring using proxy services.

Grid technologies have proven to be very successful in the area of eScience, and in particular in healthcare applications. But while the applicability of workflow enacting tools for biomedical research has long since been proven, the practical adoption into regular clinical research has some additional challenges in grid context. In this paper, we investigate the case of data monitoring, and how to seamlessly implement the step between a one-time proof-of-concept workflow and high-performance on-line monitoring of data streams, as exemplified by the case of long-running clinical trials. We will present an approach based on proxy services that allows executing single-run workflows repeatedly with little overhead.

PharmActa: Empowering Patients to Avoid Clinical Significant Drug⁻Herb Interactions.

Herbal medicinal products (HMPs) are the subject of increasing interest regarding their benefits for health. However, a serious concern is the potential appearance of clinically significant drug⁻herb interactions in patients. This work provides an overview of drug⁻herb interactions and an evaluation of their clinical significance. We discuss how personalized health services and mobile health applications can utilize tools that provide essential information to patients to avoid drug⁻HMP interactions. There is a specific mention to PharmActa, a dedicated mobile app for personalized pharmaceutical care with information regarding drug⁻HMPs interactions. Several studies over the years have shown that for some HMPs, the potential to present clinically significant interactions is evident, especially for many of the top selling HMPs. Towards that, PharmActa presents how we can improve the way that information regarding potential drug⁻herb interactions can be disseminated to the public. The utilization of technologies focusing on medical information and context awareness introduce a new era in healthcare. The exploitation of eHealth tools and pervasive mobile monitoring technologies in the case of HMPs will allow the citizens to be informed and avoid potential drug⁻HMPs interactions enhancing the effectiveness and ensuring safety for HMPs.

A semantic grid infrastructure enabling integrated access and analysis of multilevel biomedical data in support of postgenomic clinical trials on cancer.

This paper reports on original results of the Advancing Clinico-Genomic Trials on Cancer integrated project focusing on the design and development of a European biomedical grid infrastructure in support of multicentric, postgenomic clinical trials (CTs) on cancer. Postgenomic CTs use multilevel clinical and genomic data and advanced computational analysis and visualization tools to test hypothesis in trying to identify the molecular reasons for a disease and the stratification of patients in terms of treatment. This paper provides a presentation of the needs of users involved in postgenomic CTs, and presents such needs in the form of scenarios, which drive the requirements engineering phase of the project. Subsequently, the initial architecture specified by the project is presented, and its services are classified and discussed. A key set of such services are those used for wrapping heterogeneous clinical trial management systems and other public biological databases. Also, the main technological challenge, i.e. the design and development of semantically rich grid services is discussed. In achieving such an objective, extensive use of ontologies and metadata are required. The Master Ontology on Cancer, developed by the project, is presented, and our approach to develop the required metadata registries, which provide semantically rich information about available data and computational services, is provided. Finally, a short discussion of the work lying ahead is included.

Delivering a lifelong integrated electronic health record based on a service oriented architecture.

Efficient access to a citizen's Integrated Electronic Health Record (I-EHR) is considered to be the cornerstone for the support of continuity of care, the reduction of avoidable mistakes, and the provision of tools and methods to support evidence-based medicine. For the past several years, a number of applications and services (including a lifelong I-EHR) have been installed, and enterprise and regional infrastructure has been developed, in HYGEIAnet, the Regional Health Information Network (RHIN) of the island of Crete, Greece. Through this paper, the technological effort toward the delivery of a lifelong I-EHR by means of World Wide Web Consortium (W3C) technologies, on top of a service-oriented architecture that reuses already existing middleware components is presented and critical issues are discussed. Certain design and development decisions are exposed and explained, laying this way the ground for coordinated, dynamic navigation to personalized healthcare delivery.

Extending workflow management for knowledge discovery in clinico-genomic data.

Recent advances in research methods and technologies have resulted in an explosion of information and knowledge about cancers and their treatment. Knowledge Discovery (KD) is a key technique for dealing with this massive amount of data and the challenges of managing the steadily growing amount of available knowledge. In this paper, we present the ACGT integrated project, which is to contribute to the resolution of these problems by developing semantic grid services in support of multi-centric, post-genomic clinical trials. In particular, we describe the challenges of KD in clinico-genomic data in a collaborative Grid framework, and present our approach to overcome these difficulties by improving workflow management, construction and managing workflow results and provenance information. Our approach combines several techniques into a framework that is suitable to address the problems of interactivity and multiple dependencies between workflows, services, and data.

Ensuring sustainability of software tools and services by cooperation with a research infrastructure.

Sustainability of project output and especially of the maintenance and further development of software is of growing concern for the research community. In the personalized medicine project p-medicine solutions that address this sustainability problem were developed and discussed in a workshop. They involve a number of interrelated and mutually supportive measures including the creation of a service center, building modular software, using common data standards, mutual service exchange with a research infrastructure, Open Source and fee-based software provision, joint promotion and deployment of tools in a regulated, clinical trial situation. These ideas join a nascent literature seeking to understand how project output can be put into a sustainable environment and to suggest solutions that may be useful for academic projects in general.