Yaffa Rubinstein

Biospecimen Reporting for Improved Study Quality (BRISQ)

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 (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 around biospecimen-related research and help reassure patient contributors and the advocacy community that the contributions are valued and respected.

Inhibition of NF-κB Activity Enhances TRAIL Mediated Apoptosis in Breast Cancer Cell Lines

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-κB can inhibit apoptosis induced by a variety of stimuli including activation of death receptors. We investigated whether NF-κB contributes to the resistance of breast cancer cells to TRAIL induced apoptosis. All of the resistant breast cancer cell lines expressed NF-κB and had detectable NF-κB activity in nuclear extracts prior to treatment with TRAIL. Upon TRAIL treatment, a significant increase in NF-κB activity was seen in most of the cell lines. To directly test if NF-κB activity contributes to the resistance of these cell lines to TRAIL, we transiently transfected the resistant cell lines with an inhibitor of NF-κB (IκBΔN) 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 IκBΔN. These results demonstrate that TRAIL resistant breast cancer cells fail to rapidly activate the apoptotic machinery but they do activate NF-κB. Inhibition of NF-κB activity increases the sensitivity to TRAIL mediated apoptosis in resistant cells. These results suggest that agents which inhibit NF-κB should increase the clinical efficacy of TRAIL in breast cancer cells.

Chromosomal protein HMGN1 enhances the acetylation of lysine 14 in histone H3

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.

The case for a global rare-diseases registry

Rare diseases are a clinically heterogeneous group of about 6500 disorders, and in fewer than 200 000 individuals in the USA. They are commonly diagnosed during childhood, often inherited, and can have deleterious long-term eff ects. Although any one condition is rare, their cumulative public health burden is substantial, with 6–8% of people having a rare disease at some point during life. Because of the rarity, no single institution, and in many cases no single country, has suffi cient numbers of patients to do generalisable clinical and translational research. Geographic spread of patients has been a major impediment to recruitment into clinical trials. Most rare diseases do not have a specifi c International Classifi cation of Diseases code, which hampers research that uses existing databases. Before the USA, the its emphasis on public health research. Although a full analysis of all present funding for health research in India and what it is spent on is not available, the funding from both domestic and international sources has increased substantially in India over the past decade. What then are the key goals that policy should address to boost research towards health care for all in India? First, a national research tracking mech anism should be developed to guide funding and commissioning of highquality research into the major under-represented causes of disease burden and into neglected health-system issues. Second, a systematic plan is needed to make research initiatives more interactive with policies and implementation of health programmes, so that research is more relevant for the health system and policy, and the knowledge generated is used more often by policy makers. Third, rigorous evaluation research should become an essential component of all major population health programmes and policies, to understand how these could be refi ned to improve health outcomes and how the underserved segments of the Indian population could be better reached to improve health equity. For these goals to be achieved, the major national organisations attempting to strengthen health research in India should come together to provide eff ective stewardship. These organisations should collaboratively develop mechanisms that enable agreement on tangible medium-term and long-term targets for health research in the country, a plan of action, and methods to track progress in research utilisation to achieve health care for all in India. Although solutions for India will have to be tailored to its circumstances, there are useful lessons to be learnt from the systematic eff orts of other countries aimed at matching research with public health priorities to more eff ectively improve population health. *Lalit Dandona, V M Katoch, Rakhi Dandona Public Health Foundation of India, New Delhi 110070, India (LD, RD); Institute for Health Metrics and Evaluation, University of Washington, Seattle, Washington, USA (LD); and Department of Health Research and Indian Council of Medical Research, Ministry of Health and Family Welfare, Government of India, New Delhi, India (VMK) lalit.dandona@phfi .org

Role of international registries in enhancing the care of familial hypercholesterolaemia

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.

Chromosomal protein HMGN1 modulates the expression of N-cadherin.

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.

NIH/NCATS/GRDR® Common Data Elements: A leading force for standardized data collection

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.

Improving the value of clinical research through the use of Common Data Elements.

The use of Common Data Elements can facilitate cross-study comparisons, data aggregation, and meta-analyses; simplify training and operations; improve overall efficiency; promote interoperability between different systems; and improve the quality of data collection. A Common Data Element is a combination of a precisely defined question (variable) paired with a specified set of responses to the question that is common to multiple datasets or used across different studies. Common Data Elements, especially when they conform to accepted standards, are identified by research communities from variable sets currently in use or are newly developed to address a designated data need. There are no formal international specifications governing the construction or use of Common Data Elements. Consequently, Common Data Elements tend to be made available by research communities on an empiric basis. Some limitations of Common Data Elements are that there may still be differences across studies in the interpretation and implementation of the Common Data Elements, variable validity in different populations, and inhibition by some existing research practices and the use of legacy data systems. Current National Institutes of Health efforts to support Common Data Element use are linked to the strengthening of National Institutes of Health Data Sharing policies and the investments in data repositories. Initiatives include cross-domain and domain-specific resources, construction of a Common Data Element Portal, and establishment of trans-National Institutes of Health working groups to address technical and implementation topics. The National Institutes of Health is seeking to lower the barriers to Common Data Element use through greater awareness and encourage the culture change necessary for their uptake and use. As National Institutes of Health, other agencies, professional societies, patient registries, and advocacy groups continue efforts to develop and promote the responsible use of Common Data Elements, particularly if linked to accepted data standards and terminologies, continued engagement with and feedback from the research community will remain important.

Current trends in biobanking for rare diseases: a review

License. The full terms of the License are available at http://creativecommons.org/licenses/by-nc/3.0/. Non-commercial uses of the work are permitted without any further permission from Dove Medical Press Limited, provided the work is properly attributed. Permissions beyond the scope of the License are administered by Dove Medical Press Limited. Information on how to request permission may be found at: http://www.dovepress.com/permissions.php Journal of Biorepository Science for Applied Medicine 2014:2 49–61 Journal of Biorepository Science for Applied Medicine Dovepress

The risk of re-identification versus the need to identify individuals in rare disease research

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.