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The premise of Open Science is that research and medical management will progress faster if data and knowledge are openly shared. The value of Open Science is nowhere more important and appreciated than in the rare disease (RD) community. Research into RDs has been limited by insufficient patient data and resources, a paucity of trained disease experts, and lack of therapeutics, leading to long delays in diagnosis and treatment. These issues can be ameliorated by following the principles and practices of sharing that are intrinsic to Open Science. Here, we describe how the RD community has adopted the core pillars of Open Science, adding new initiatives to promote care and research for RD patients and, ultimately, for all of medicine. We also present recommendations that can advance Open Science more globally. This work was supported by the U.S. Department of Health and Human Services National Institutes of Health (5r24od011883), National Institutes of Health (NIH) Office of the Director (OD); the Monarch Initiative (1R24OD011883) and the Eunice Kennedy Shriver National Institute of Child Health and Human Development (U54 HD079123). Sí

Introduction: There are currently several strategies developed to facilitate access and data sharing in the rare disease field. These strategies have paid special attention to the importance of rare disease patient registries and biobanks, as they are essential tools for surveillance and the provision of biosamples and phenotypic and genetic data for research worldwide. However, they are usually fragmented by disease, data model and country. Moreover, these resources have restricted access in order to protect privacy of patient data.Areas covered: This article is an overview of existing initiatives that facilitate access to rare disease patient registries and biobanks, future challenges of accessing data/biosamples and the major barriers to achieve interoperability and worldwide sharing.Expert opinion: RD patient registries and biobanks play an important role in the discovery of either new rare diseases or new phenotype-genotype correlations. However, there is still little access to data and impor...

Rare diseases (RD) patient registries are powerful instruments that help develop clinical research, facilitate the planning of appropriate clinical trials, improve patient care, and support healthcare management. They constitute a key information system that supports the activities of European Reference Networks (ERNs) on rare diseases. A rapid proliferation of RD registries has occurred during the last years and there is a need to develop guidance for the minimum requirements, recommendations and standards necessary to maintain a high-quality registry. In response to these heterogeneities, in the framework of RD-Connect, a European platform connecting databases, registries, biobanks and clinical bioinformatics for rare disease research, we report on a list of recommendations, developed by a group of experts, including members of patient organizations, to be used as a framework for improving the quality of RD registries. This list includes aspects of governance, Findable, Accessible, Interoperable and Reusable (FAIR) data and information, infrastructure, documentation, training, and quality audit. The list is intended to be used by established as well as new RD registries. Further work includes the development of a toolkit to enable continuous assessment and improvement of their organizational and data quality. Supported by the RD-CONNECT: an integrated platform connecting registries, biobanks and clinical bioinformatics for rare disease research, which received funding from the European Union within the framework of FP7 Collaborative projectHEALTH.2012.2.1.1-1-C [Grant agreement number: 305444]. Supported partly also by EuRRECa: European Registries for Rare Endocrine Conditions, which received funding from the European Union within the framework of CHAFEA Health Programme (2014–2020) [Grant agreement number: 777215] and the COST Action CA16210 “Maximising Impact of research in NeuroDevelopmental Disorders”. Sí

In rare disease (RD) research, there is a huge need to systematically collect biomaterials, phenotypic, and genomic data in a standardized way and to make them findable, accessible, interoperable and reusable (FAIR). RD-Connect is a 6 years global infrastructure project initiated in November 2012 that links genomic data with patient registries, biobanks, and clinical bioinformatics tools to create a central research resource for RDs. Here, we present RD-Connect Registry & Biobank Finder, a tool that helps RD researchers to find RD biobanks and registries and provide information on the availability and accessibility of content in each database. The finder concentrates information that is currently sparse on different repositories (inventories, websites, scientific journals, technical reports, etc.), including aggregated data and metadata from participating databases. Aggregated data provided by the finder, if appropriately checked, can be used by researchers who are trying to estimate the prevalence of a RD, to organize a clinical trial on a RD, or to estimate the volume of patients seen by different clinical centers. The finder is also a portal to other RD-Connect tools, providing a link to the RD-Connect Sample Catalogue, a large inventory of RD biological samples available in participating biobanks for RD research. There are several kinds of users and potential uses for the RD-Connect Registry & Biobank Finder, including researchers collaborating with academia and the industry, dealing with the questions of basic, translational, and/or clinical research. As of November 2017, the finder is populated with aggregated data for 222 registries and 21 biobanks. This work has been supported by the European Union Seventh Framework Programme (FP7/20072013) under grant agreements no. 305444 (RD-Connect). RD-Connect has a main role in funding authors contributing to the study design, data collection and analysis, decision to publish, or preparation of the manuscrip. NeurOmics (no. 305121, http://rd-neuromics.eu/) and EURenOmics (no. 305608, http://www.eurenomics.eu/) have had mainly a role of data providers, since several registries participating to the Registry & Biobank Finder collaborate with the two projects. We thank ODEX4all (NWO 650.002.002), ELIXIR funded through participating member states, and ELIXIR-EXCELERATE funded through the European Commission within the Research Infrastructures Programme of Horizon 2020 (grant agreement number 676559) for collaborating to the study design and software development especially with a view to interoperability with other systems (MR, MT). MF and MM are funded by Fondazione Telethon (Project GTB12001; Telethon Network of Genetic Biobanks). Sí

In the field of rare diseases, registries are considered power tool to develop clinical research, to facilitate the planning of appropriate clinical trials, to improve patient care and healthcare planning. Therefore high quality data of rare diseases registries is considered to be one of the most important element in the establishment and maintenance of a registry. Data quality can be defined as the totality of features and characteristics of data set that bear on its ability to satisfy the needs that result from the intended use of the data. In the context of registries, the 'product' is data, and quality refers to data quality, meaning that the data coming into the registry have been validated, and ready for use for analysis and research. Determining the quality of data is possible through data assessment against a number of dimensions: completeness, validity; coherence and comparability; accessibility; usefulness; timeliness; prevention of duplicate records. Many others factors may influence the quality of a registry: development of standardized Case Report Form and security/safety controls of informatics infrastructure. With the growing number of rare diseases registries being established, there is a need to develop a quality validation process to evaluate the quality of each registry. A clear description of the registry is the first step when assessing data quality or the registry evaluation system. Here we report a template as a guide for helping registry owners to describe their registry.

Well-annotated and properly preserved specimens are crucial both for diagnostic purposes and for use in basic and pre-clinical research, and are especially important for rare disease (RD) studies. Several consortia have been established in the recent years in order to facilitate research and to maximise access to rare biological samples and data stored in rare disease biobanks and registries, among them the EuroBioBank network and the Spain National Rare Disease Registry (RDR) and Biobank (BioNER).EuroBioBank, established in 2001, was the first network of RD biobanks to operate in Europe as a service distributing human DNA, cells, and tissue to the scientific community conducting research on rare diseases.The Spanish RDR and BioNER were created for facilitating rare disease research and health-related matters. The coordination of these two bodies represents an example of great scientific value as biological samples donated by patients at BioNER are linked to clinical information collected in the RDR.Rare disease biobanks and registries will need for the future to increase their effort to improve interconnection so to enable investigators to better locate samples and associated data, while protecting security of the data and privacy of the participants and adhering to international ethical and legal requirements.

Rare disease registries have now been recognized as a global priority for progress both in monitoring and documenting the natural course, and preventing and treating rare diseases. However, a disease registry is only one element of rare disease translational research. Here, we outline what we believe are ten key components in comprehensive rare disease translational research and describe critical relationships between them. These components are: (i) client–practitioner partnerships; (ii) disease registries; (iii) biobanks; (iv) genomics and other -omics platforms; (v) community-based and population-wide studies; (vi) bioinformatics and high performance computing; (vii) interactions with pharma to facilitate drug discovery; (viii) personalized treatments based on genotype-phenotype correlations; (ix) eHealth and a whole of life record; and (x) regulatory frameworks, particularly with regard to specimen and data sharing, and the return of results. Each component has its own inherent complexity, but if effectively integrated they will provide a comprehensive approach to the future management of rare diseases, and aid health care providers in delivering services to individuals affected with rare diseases. We demonstrate that navigation through the roadmap can provide relevant health stakeholders with a blueprint to understand the challenges and barriers which need to be overcome within and across the constituent components. The rare disease roadmap will assist decision-making at all health stakeholder levels and enable the seamless integration of new knowledge, standard operating procedures and the implementation of best practice.

The main goal of the NIH/NCATS GRDR® program is to serve as a central web-based global data repository to integrate de-identified patient clinical data from rare disease registries, and other data sources, in a standardized manner, to be available to researchers for conducting various biomedical studies, including clinical trials and to support analyses within and across diseases. The aim of the program is to advance research for many rare diseases. One of the first tasks toward achieving this goal was the development of a set of Common Data Elements (CDEs), which are controlled terminologies that represent collected data. A list of 75 CDEs was developed by a national committee and was validated and implemented during a period of 2 year proof of concept. Access to GRDR CDEs is freely available at: https://grdr.ncats.nih.gov/index.php?option=com_content&view=article&id=3&Itemid=5. The GRDR CDEs have been the cornerstone of the GRDR repository, as well as of several other national and international patient registries. The establishment of the GRDR program has elevated the issue of data standardization and interoperability for rare disease patient registries, to international attention, resulting in a global dialog and significant change in the mindset of registry developers, patient advocacy groups, and other national and international organizations.

Familial hypercholesterolaemia (FH) is a relatively common genetic disorder associated with high risk of coronary heart disease that is preventable by early diagnosis and treatment. In a previous article, we reviewed the evidence for clinical management, models of care and health economic evaluations. The present commentary emphasises that collective action is needed to strengthen our approaches to evidence-based care, including better diagnosis and access to effective therapies. We detail how contemporary innovations in inter-operable, web-based, open-source and secure registries can provide the supporting infrastructure to: (i) address a current gap in the flow of data for measuring the quality of healthcare; (ii) support basic research through provision of high-quality, de-identified aggregate data; (iii) enable equitable access to clinical trials; and (iv) support efforts to disseminate evidence for best practice and information for care services. We describe how these aspects of enabling infrastructure will be incorporated into the development of a National FH Registry for Australasia, and proffer that a coordinated response to FH would be enhanced through a global network of inter-operable registries.

In the field of rare diseases, registries are considered power tool to develop clinical research, to facilitate the planning of appropriate clinical trials, to improve patient care and healthcare planning. Therefore high quality data of rare diseases registries is considered to be one of the most important element in the establishment and maintenance of a registry. Data quality can be defined as the totality of features and characteristics of data set that bear on its ability to satisfy the needs that result from the intended use of the data. In the context of registries, the 'product' is data, and quality refers to data quality, meaning that the data coming into the registry have been validated, and ready for use for analysis and research. Determining the quality of data is possible through data assessment against a number of dimensions: completeness, validity; coherence and comparability; accessibility; usefulness; timeliness; prevention of duplicate records. Many others factors may influence the quality of a registry: development of standardized Case Report Form and security/safety controls of informatics infrastructure. With the growing number of rare diseases registries being established, there is a need to develop a quality validation process to evaluate the quality of each registry. A clear description of the registry is the first step when assessing data quality or the registry evaluation system. Here we report a template as a guide for helping registry owners to describe their registry.

Well-annotated and properly preserved specimens are crucial both for diagnostic purposes and for use in basic and pre-clinical research, and are especially important for rare disease (RD) studies. Several consortia have been established in the recent years in order to facilitate research and to maximise access to rare biological samples and data stored in rare disease biobanks and registries, among them the EuroBioBank network and the Spain National Rare Disease Registry (RDR) and Biobank (BioNER).

There is a growing concern in the ethics literature and among policy makers that de-identification or coding of personal data and biospecimens is not sufficient for protecting research subjects from privacy invasions and possible breaches of confidentiality due to the possibility of unauthorized re-identification. At the same time, there is a need in medical science to be able to identify individual patients. In particular for rare disease research there is a special and well-documented need for research collaboration so that data and biosamples from multiple independent studies can be shared across borders. In this article, we identify the needs and arguments related to de-identification and re-identification of patients and research subjects and suggest how the different needs may be balanced within a framework of using unique encrypted identifiers. Funding for this research was received by the European Union Seventh Framework Programme (FP7/2007-2013) under grant agreement No. 305444 (RD-Connect) and 305121 (Neuromics). Hansson also received funding by the Innovative Medicines Initiative project BT-Cure (grant agreement number 115142-1), the BioBanking and Molecular Resource Infrastructure of Sweden project (financed by the Swedish Research Council), and the European Union Seventh Framework Programmes Euro-TEAM, BiobankCloud and BBMRI-LPC. Dawkins acknowledges support-in-part from the Australian National Health and Medical Research Council RD-Connect project APP1055319 under the NHMRC–European Union Collaborative Research Grants scheme. Sí

a Office of Rare Diseases Research, National Institutes of Health, Bethesda, MD, United States b Office of the Clinical Director, National Human Genome Research Institute, Department of Bioethics, Clinical Center, National Institutes of Health, Bethesda, MD, United States c Department of Health and Human Services, Office for Human Research Protections, Rockville, MD, United States d Combined NeuroScience Institutional Review Board, National Institute of Health, Bethesda, MD, United States e Office of Biorepositories and Biospecimen Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, United States f Case Western University, Cleveland, OH, United States g University of Rochester School of Medicine and Dentistry, Rochester, NY, United States h Patient Crossroads, Innolyst, Inc., San Mateo, CA, United States i University of Maryland School of Law, College Park, MD, United States

A December 2010 meeting, “Down Syndrome: National Conference on Patient Registries, Research Databases, and Biobanks,” was jointly sponsored by the Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD) at the National Institutes of Health (NIH) in Bethesda, MD, and the Global Down Syndrome Foundation (GDSF)/Linda Crnic Institute for Down Syndrome based in Denver, CO. Approximately 70 attendees and organizers from various advocacy groups, federal agencies (Centers for Disease Control and Prevention, and various NIH Institutes, Centers, and Offices), members of industry, clinicians, and researchers from various academic institutions were greeted by Drs. Yvonne Maddox, Deputy Director of NICHD, and Edward McCabe, Executive Director of the Linda Crnic Institute for Down Syndrome. They charged the participants to focus on the separate issues of contact registries, research databases, and biobanks through both podium presentations and breakout session discussions. Among the breakout groups for each of the major sessions, participants were asked to generate responses to questions posed by the organizers concerning these three research resources as they related to Down syndrome and then to report back to the group at large with a summary of their discussions. This report represents a synthesis of the discussions and suggested approaches formulated by the group as a whole.

A movement to create a global patient registry for as many as 7,000 rare diseases was launched at a workshop, "Advancing Rare Disease Research: The Intersection of Patient Registries, Biospecimen Repositories, and Clinical Data." http://rarediseases.info.nih.gov/PATIENT_REGISTRIES_WORKSHOP/. The workshop was sponsored by the Office of Rare Diseases Research (ORDR). The focus was the building of an infrastructure for an internet-based global registry linking to biorepositories. Such a registry would serve the patients, investigators, and drug companies. To aid researchers the participants suggested the creation of a centralized database of biorepositories for rare biospecimens (RD-HUB)http://biospecimens.ordr.info.nih.gov/ that could be linked to the registry. Over two days of presentations and breakout sessions, several hundred attendees discussed government rules and regulations concerning privacy and patients' rights and the nature and scope of data to be entered into a central registry as well as concerns about how to validate patient and clinician-entered data to ensure data accuracy. Mechanisms for aggregating data from existing registries were also discussed. The attendees identified registry best practices, model coding systems, international systems for recruiting patients into clinical trials and novel ways of using the internet directly to invite participation in research. They also speculated about who would bear ultimate responsibility for the informatics in the registry and who would have access to the information. Hurdles associated with biospecimen collection and how to overcome them were detailed. The development of the recommendations was, in itself, an indication of the commitment of the rare disease community as never before.

HMGN1 is a nuclear protein that binds to nucleosomes and alters the accessibility of regulatory factors to their chromatin targets. To elucidate its biological function and identify specific HMGN1 target genes, we generated Hmgn1–/– mice. DNA microarray analysis of Hmgn1+/+ and Hmgn1–/– embryonic fibroblasts identified N-cadherin as a potential HMGN1 gene target. RT-PCR and western blot analysis confirmed a linkage between HMGN1 expression and N-cadherin levels. In both transformed and primary mouse embryonic fibroblasts (MEFs), HMGN1 acted as negative regulator of N-cadherin expression. Likewise, the N-cadherin levels in early embryos of Hmgn1–/– mice were higher than those of their Hmgn1+/+ littermates. Loss of HMGN1 increased the adhesiveness, motility and aggregation potential of Hmgn1–/– MEFs, a phenotype consistent with increased levels of N-cadherin protein. Re-expression of wild-type HMGN1, but not of the mutant HMGN1 protein that does not bind to chromatin, in Hmgn1–/– MEFs, decreased the levels of N-cadherin and restored the Hmgn1+/+ phenotype. These studies demonstrate a role for HMGN1 in the regulation of specific gene expression. We suggest that in MEFs, and during early mouse development, the interaction of HMGN1 with chromatin down-regulates the expression of N-cadherin.

The acetylation levels of lysine residues in nucleosomes, which are determined by the opposing activities of histone acetyltransferases (HATs) and deacetylases, play an important role in regulating chromatin-related processes, including transcription. We report that HMGN1, a nucleosomal binding protein that reduces the compaction of the chromatin fiber, increases the levels of acetylation of K14 in H3. The levels of H3K14ac in Hmgn1-/- cells are lower than in Hmgn1+/+ cells. Induced expression of wild-type HMGN1, but not of a mutant that does not bind to chromatin, in Hmgn1-/- cells elevates the levels of H3K14ac. In vivo, HMGN1 elevates the levels of H3K14ac by enhancing the action of HAT. In vitro, HMGN1 enhances the ability of PCAF to acetylate nucleosomal, but not free, H3. Thus, HMGN1 modulates the levels of H3K14ac by binding to chromatin. We suggest that HMGN1, and perhaps similar architectural proteins, modulates the levels of acetylation in chromatin by altering the equilibrium generated by the opposing enzymatic activities that continuously modify and de-modify the histone tails in nucleosomes.

There is a growing international agreement on the need to provide greater access to research data and bio-specimen collections to optimize their long-term value and exploit their potential for health discovery and validation. This is especially evident for rare disease research. Currently, the rising value of data and bio-specimen collections does not correspond with an equal increase in data/sample-sharing and data/sample access. Contradictory legal and ethical frameworks across national borders are obstacles to effective sharing: more specifically, the absence of an integrated model proves to be a major logistical obstruction. The Charter intends to amend the obstacle by providing both the ethical foundations on which data sharing should be based, as well as a general Material and Data Transfer Agreement (MTA/DTA). This Charter is the result of a careful negotiation of different stakeholders' interest and is built on earlier consensus documents and position statements, which provided the general international legal framework. Further to this, the Charter provides tools that may help accelerate sharing. The Charter has been formulated to serve as an enabling tool for effective and transparent data and bio-specimen sharing and the general MTA/DTA constitutes a mechanism to ensure uniformity of access across projects and countries, and may be regarded as a consistent basic agreement for addressing data and material sharing globally. The Charter is forward looking in terms of emerging issues from the perspective of a multi-stakeholder group, and where possible, provides strategies that may address these issues.

Success rates for genomic analyses of highly heterogeneous disorders can be greatly improved if a large cohort of patient data is assembled to enhance collective capabilities for accurate sequence variant annotation, analysis, and interpretation. Indeed, molecular diagnostics requires the establishment of robust data resources to enable data sharing that informs accurate understanding of genes, variants, and phenotypes. The "Mitochondrial Disease Sequence Data Resource (MSeqDR) Consortium" is a grass-roots effort facilitated by the United Mitochondria] Disease Foundation to identify and prioritize specific genomic data analysis needs of the global mitochondrial disease clinical and research community. A central Web portal (https://mseqdr.org) facilitates the coherent compilation, organization, annotation, and analysis of sequence data from both nuclear and mitochondrial genomes of individuals and families with suspected mitochondria! disease. This Web portal provides users with a flexible and expandable suite of resources to enable variant-, gene-, and exome-level sequence analysis in a secure, Web-based, and user-friendly fashion. Users can also elect to share data with other MSeqDR Consortium members, or even the general public, either by custom annotation tracks or through the use of a convenient distributed annotation system (DAS) mechanism. A range of data visualization and analysis tools are provided to facilitate user interrogation and understanding of genomic, and ultimately phenotypic, data of relevance to mitochondrial biology and disease. Currently available tools for nuclear and mitochondrial gene analyses include an MSeqDR GBrowse instance that hosts optimized mitochondrial disease and mitochondrial DNA (mtDNA) specific annotation tracks, as well as an MSeqDR locus-specific database (LSDB) that curates variant data on more than 1300 genes that have been implicated in mitochondrial disease and/or encode mitochondria-localized proteins. MSeqDR is integrated with a diverse array of mtDNA data analysis tools that are both freestanding and incorporated into an online exome-level dataset curation and analysis resource (GEM.app) that is being optimized to support needs of the MSeqDR community. In addition, MSeqDR supports mitochondrial disease phenotyping and ontology tools, and provides variant pathogenicity assessment features that enable community review, feedback, and integration with the public ClinVar variant annotation resource. A centralized Web-based informed consent process is being developed, with implementation of a Global Unique Identifier (GUID) system to integrate data deposited on a given individual from different sources. Community-based data deposition into MSeqDR has already begun. Future efforts will enhance capabilities to incorporate phenotypic data that enhance genomic data analyses. MSeqDR will fill the existing void in bioinformatics tools and centralized knowledge that are necessary to enable efficient nuclear and mtDNA genomic data interpretation by a range of shareholders across both clinical diagnostic and research settings. Ultimately, MSeqDR is focused on empowering the global mitochondrial disease community to better define and explore mitochondrial diseases. (C) 2014 Elsevier Inc. All rights reserved.

Cbl proteins function as ubiquitin protein ligases for the activated epidermal growth factor receptor and, thus, negatively regulate its activity. Here we show that Cbl-b is ubiquitinated and degraded upon activation of the receptor. Epidermal growth factor (EGF)-induced Cbl-b degradation requires intact RING finger and tyrosine kinase binding domains and requires binding of the Cbl-b protein to the activated EGF receptor (EGFR). Degradation of both the EGFR and the Cbl-b protein is blocked by lysosomal and proteasomal inhibitors. Other components of the EGFR-signaling complex (i.e. Grb2 and Shc) are also degraded in an EGF-induced Cbl-b-dependent fashion. Our results suggest that the ubiquitin protein ligase function of Cbl-b is regulated by coordinated degradation of the Cbl-b protein along with its substrate. Furthermore, the data demonstrate that Cbl-b mediates degradation of multiple proteins in the EGFR-signaling complex.

Most breast cancer cell lines are resistant to TNF-related apoptosis inducing ligand (TRAIL) induced apoptosis. In sensitive breast cancer cell lines TRAIL rapidly induces the cleavage and activation of caspases leading to the subsequent cleavage of downstream caspase substrates. In contrast, there is no caspase activation in the resistant cell lines. The transcription factor NF-KB can inhibit apoptosis induced by a variety of stimuli including activation of death receptors. We investigated whether NF-kappaB contributes to the resistance of breast cancer cells to TRAIL induced apoptosis. All of the resistant breast cancer cell lines expressed NF-kappaB and had detectable NF-kappaB activity in nuclear extracts prior to treatment with TRAIL. Upon TRAIL treatment, a significant increase in NF-kappaB activity was seen in most of the cell lines. To directly test if NF-kappaB activity contributes to the resistance of these cell lines to TRAIL, we transiently transfected the resistant cell lines with an inhibitor of NF-kappaB (IkappaBdeltaN) and measured TRAIL induced apoptosis in control and transfected cells. All of the resistant cell lines tested showed an increase in TRAIL induced apoptosis when transfected with the IKBdeltaN. These results demonstrate that TRAIL resistant breast cancer cells fail to rapidly activate the apoptotic machinery but they do activate NF-kappaB. Inhibition of NF-kappaB activity increases the sensitivity to TRAIL mediated apoptosis in resistant cells. These results suggest that agents which inhibit NF-kappaB should increase the clinical efficacy of TRAIL in breast cancer cells.

Studies in C. elegans and Drosophila melanogaster suggest that cbl proteins are inhibitors of epidermal growth factor receptor (EGFR) function. Here we describe that overexpression of cbl-b, a homologue of the c-cbl protooncogene, inhibits EGFR-induced apoptosis in MDA-MB-468 breast cancer cells. Overexpression of cbl-b results in a shortened duration of EGFR activation upon EGF stimulation. This is demonstrated by decreased amounts of phosphorylated EGFR as well as by inhibition of multiple downstream signaling pathways. The inhibition of signaling by cbl-b results from increased ubiquitination and degradation of the activated EGFR. The inhibitory effects of cbl-b overexpression on apoptosis and on EGFR signaling are reversed by blocking proteosomal degradation of the EGFR. These data demonstrate that the mechanism by which cbl-b inhibits EGFR-induced apoptosis is by activation-dependent degradation of the EGFR. They imply that this mechanism may be a general one whereby cbl proteins regulate intracellular signaling.

Rare diseases (RD) refer to a collection of approximately 5,000–8,000 individual diseases that have a low prevalence and are often genetic in origin. While RD can manifest throughout life, they frequently affect children and newborns. Common characteristics include being severe, disabling, life-threatening, degenerative and affecting different organ systems. The burden of RD is often exacerbated by a lack of specific treatments. Whilst there is etiological heterogeneity, there is overlap in cellular and molecular pathways. Amongst specialists, there is legitimate hope that based on genetic knowledge and pathway definition, a new medical classification system, currently called “precision medicine”, will be developed, which may change our view on how to apply shared therapeutic targets. Thus, collection of clinical and genetic data and biospecimens (in biobanks) will play an increasing role in diagnoses and development of therapies for RD. Biobanks are maintained collaboratively by researchers or their institutions, and involve a delicate balance between health policy objectives, academic research, public good outcomes, and community trust. Due to the nature of RD, international cooperation is critical for sharing limited numbers of RD samples and achieving a critical mass. Here we review the current and future direction of RD biobanks and discuss research and development stemming from the use of biospecimens to improve management of RD. The authors acknowledge the financial support of the European Union Seventh Framework Programme (FP7/2007–2013) under grant agreement numbers 305444 (RD-Connect), 305608 (EURenOmics), and 305121 (NeurOmics); TREAT-NMD operating grants, FP6 LSHM-CT-2006-036825, 20123307 UNEW_FY2013; Telethon grant GTB12001 to TNGB, and AFM 16104; EUROPLAN 2012–2015, coordinated by Italian National Institute of Health-Italian National Centre for Rare Diseases, included in the EUCERD Joint Action (grant number 2011 22 01, cofunded by the European Union Commission (DG-SANCO); Office of Rare Diseases Research at National Center for Advancing Translational Sciences/National Institutes of Health; European Organisation for Rare Diseases; Biobanking and Biomolecular Resources Research Infrastructure (BBMRI-ERIC); ISBER/ESBB Rare Diseases Working Group; and Public Population Project in Genomics and Society (P3G). Sí

Informed consent is a fundamental ethical requirement in most clinical research. Much has been written about the benefits and barriers of research-related informed consent from patients prior to participating in medical research studies. Consent templates and examples exist and are widely available for use by organizations or individual investigators. Appropriately designed templates provide the required elements as mandated by federal regulations and international standards. Nonetheless, research consent forms are often long and complex and not always useful to participant understanding. In order to initiate, conduct and complete meaningful studies on rare diseases in an appropriate time frame, it is necessary to identify and locate patients with rare diseases who may be dispersed over large geographical areas. Patient registries are becoming an important tool and resource to accelerate patient recruitment into clinical trials and other medical studies designed to evaluate diagnostics and therapeutics with the hope of eventually effectively treating or curing the millions of people suffering from rare diseases. As more and more patient registries are being developed by patient advocacy groups, research investigators, industry, and other organizations, they are faced with the challenge of the appropriate process for obtaining consent from patients to include their medical histories or donated biospecimens in the patient registries. Importantly, obtaining consent for including patient information and specimens in a registry can be different than obtaining consent for clinical trials or other medical studies that registry patients might ultimately be invited to enroll in. Whether and how extensively federal regulations, such as those found in the Common Rule or HIPAA apply to the establishment of a patient registry will depend on the context in which medical information and specimens are collected, how they will be stored, and other related factors. The literature and guidance regarding obtaining consent for participation in patient registries are evolving. Organizations and patient advocacy groups involved in the process of establishing patient registries may be faced with uncertainties regarding the necessary elements and content of informed consent documents. One of the challenges is ensuring that participants receive the information they need to make an informed decision about participating in the registry. Although the information provided and the requirements for obtaining consent from participants when establishing a patient registry may not be as stringent as consent for participating in a clinical research study, efforts should be made to develop a consent process that adequately informs patients about the purpose for joining the registry, how the registry will be used, and how the confidentiality of their information will be protected. There is an urgent need in the rare disease community for further discussions among the various stake holders about the process of obtaining consent for participation in a patient registry. Stake holders should work together to develop sets of recommendations for informed consent language and processes that can be adopted by the many different developers of patient registries. As is true for consent forms for individual clinical research studies, informed consent for participating in a patient registry is dependent upon the intended uses for data gathered and analyzed in the patient registry. One consent form cannot fit all the different registries being developed by different entities. In addition, the consent form is only part of the process of consent. For many rare diseases, adequate information may not exist and may need to be developed and provided to patients (and their family members as appropriate) as part of an ongoing consent process. Providing additional information beyond what can be presented in a written consent form may be essential in order to obtain meaningful consent from participants. The rare diseases community should work together to address these issues and develop templates and recommendations for obtaining the informed consent of patients, facilitating participation in patient registries, and adequately protecting the information provided. Guidance and recommendations regarding points to consider and information to include in developing a consent process and the consent form would be very helpful to rare disease patient advocacy organizations and others when establishing patient registries. In addition, development and utilization of common templates would facilitate global harmonization necessary to exchanging, sharing, and aggregating de-identified patient medical information from patients around the world for future studies which is so desired by the rare disease community.

Human biospecimens are subject to a number of different collection, processing, and storage factors that can significantly alter their molecular composition and consistency. These biospecimen preanalytical factors, in turn, influence experimental outcomes and the ability to reproduce scientific results. Currently, the extent and type of information specific to the biospecimen preanalytical conditions reported in scientific publications and regulatory submissions varies widely. To improve the quality of research utilizing human tissues, it is critical that information regarding the handling of biospecimens be reported in a thorough, accurate, and standardized manner. The Biospecimen Reporting for Improved Study Quality recommendations outlined herein are intended to apply to any study in which human biospecimens are used. The purpose of reporting these details is to supply others, from researchers to regulators, with more consistent and standardized information to better evaluate, interpret, compare, and reproduce the experimental results. The Biospecimen Reporting for Improved Study Quality guidelines are proposed as an important and timely resource tool to strengthen communication and publications around biospecimen-related research and help reassure patient contributors and the advocacy community that the contributions are valued and respected.

Human biospecimens are subjected to collection, processing, and storage that can significantly alter their molecular composition and consistency. These biospecimen preanalytical factors, in turn, influence experimental outcomes and the ability to reproduce scientific results. Currently, the extent and type of information specific to the biospecimen preanalytical conditions reported in scientific publications and regulatory submissions varies widely. To improve the quality of research that uses human tissues, it is crucial that information on the handling of biospecimens be reported in a thorough, accurate, and standardized manner. The Biospecimen Reporting for Improved Study Quality (BRISQ) recommendations outlined herein are intended to apply to any study in which human biospecimens are used. The purpose of reporting these details is to supply others, from researchers to regulators, with more consistent and standardized information to better evaluate, interpret, compare, and reproduce the experimental results. The BRISQ guidelines are proposed as an important and timely resource tool to strengthen communication and publications on biospecimen-related research and to help reassure patient contributors and the advocacy community that their contributions are valued and respected. Cancer (Cancer Cytopathol) 2011;119:92-101. Published 2011 by the American Cancer Society.*

HMGN1 is a nuclear protein that binds to nucleosomes and alters the accessibility of regulatory factors to their chromatin targets. To elucidate its biological function and identify specific HMGN1 target genes, we generated Hmgn1-/- mice. DNA microarray analysis of Hmgn1+/+ and Hmgn1-/- embryonic fibroblasts identified N-cadherin as a potential HMGN1 gene target. RT-PCR and western blot analysis confirmed a linkage between HMGN1 expression and N-cadherin levels. In both transformed and primary mouse embryonic fibroblasts (MEFs), HMGN1 acted as negative regulator of N-cadherin expression. Likewise, the N-cadherin levels in early embryos of Hmgn1-/- mice were higher than those of their Hmgn1+/+ littermates. Loss of HMGN1 increased the adhesiveness, motility and aggregation potential of Hmgn1-/- MEFs, a phenotype consistent with increased levels of N-cadherin protein. Re-expression of wild-type HMGN1, but not of the mutant HMGN1 protein that does not bind to chromatin, in Hmgn1-/- MEFs, decreased the levels of N-cadherin and restored the Hmgn1+/+ phenotype. These studies demonstrate a role for HMGN1 in the regulation of specific gene expression. We suggest that in MEFs, and during early mouse development, the interaction of HMGN1 with chromatin down-regulates the expression of N-cadherin.

Graham CE, Molster C, Baynam GS, et al. Journal of Biorepository Science for Applied Medicine. 2014;2:49–61.Author Deborah Mascalzoni from the Centre for Research Ethics and Bioethics, Department of Public Health and Caring Sciences, Uppsala University, Uppsala, Sweden, was erroneously left off the author list, please see the correct list here.Caroline E GrahamCaron MolsterGareth S BaynamKate BushbyMats HanssonDeborah MascalzoniAnna KoleMarina MoraLucia MonacoMatthew BellgardDavid CarpentieriManuel PosadaOlaf RiessYaffa R RubinsteinFranz SchaeferDomenica TaruscioSharon F TerryKurt ZatloukalBartha KnoppersHanns LochmüllerHugh JS Dawkins Read the original article

The role of the interferon regulatory factory (IRF) family of transcription factors in regulation of interferon alpha and interferon tau antiviral activity was investigated using a dominant negative mutant of IRF-2. The IRF-2 DNA binding domain (DBD), without the C-terminal regulatory region, was stably transfected into myeloid U937 cells. Expression of the IRF-2 DBD resulted in an increase in constitutive 2'5' oligoadenylate synthetase (OAS) levels, indicative of an active repressive mechanism, but was not sufficient to protect cells from challenge with vesicular stomatitis virus. Treatment of the DBD clones with interferons alpha A and tau failed to upregulate 2'5' OAS expression and did not elicit an antiviral response. While interferon alpha A was more sensitive than interferon tau to the inhibitory effects of the IRF-2 DBD, IRF-mediated gene induction is involved in successful interferon alpha and tau-induced anti-VSV activity.