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Biobanks' activity is based not only on securing the technology of collecting and storing human biospecimen, but also on preparing formal documentation that will enable its safe use for scientific research. In that context, the issue of informed consent, the reporting of incidental findings and the use of Transfer Agreements remain a vast challenge. This paper aims to offer first-hand tangible solutions on those issues in the context of collaborative and transnational biobanking research. It presents a four-step checklist aiming to facilitate researchers on their compliance with applicable legal and ethical guidelines, when designing their studies, when recruiting participants, when handling samples and data, and when communicating research results and incidental findings. Although the paper reflects the outcomes of the H2020 B3Africa project and examines the transfers from and to the EU as a case study, it presents a global checklist that can be used beyond the EU.
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BACKGROUND: Biobanking is an area of scientific activity that is growing in strength and importance. The variety of collections combining biological samples and medical scientific information makes biobanking an indispensable tool in the development of modern medicine. In 2016, Poland, a country with one of the largest populations in Europe, joined the Biobanking and BioMolecular resources Research Infrastructure-European Research Infrastructure Consortium (BBMRI-ERIC) to facilitate access to quality-defined human disease-relevant biological resources. This push led to the development of the Polish Biobanking Network. The purpose of this paper is to present the current state of biobanks in Poland in the context of their location, nature and resources. METHODS: To obtain information about and overall characteristics of Polish entities dealing with biobanking biological material, the dedicated Information Survey was designed. The survey was prepared in an electronic form and consisted of 53 questions-both open and closed, single and multiple choice-with some questions depending on each other. Sixty-five Polish biobanks/biorepositories participated in the survey. RESULTS: Polish biobanks are mostly affiliated with research entities (universities-42% and research institutes-30%). The data collected indicate that a considerable number of Polish biobanks are specialized (33 units), in contrast to population-based biobanks (8 units). These biobanks are mostly focused on collecting samples from oncological (23 biobanks) and rare diseases (12 biobanks). In general, great diversity was found in the material collected. Scientists working in Polish biobanks are very open to scientific cooperation (declared by 60% of units) and sharing their collections with the international scientific environment. In terms of quality issues, most biobanks declared that their quality management system was in the process of implementation (45%) or had already been implemented (23%). CONCLUSIONS: Although biobanking in Poland is still in its infancy, the results of this study seem promising and may be valuable to the wider biobanking research community. The distribution of biobanks throughout the Polish territory, their connection with scientific and clinical units, and their involvement in research on rare diseases may contribute to an increase in the number of multicenter studies.
Subject(s)
Biological Specimen Banks , Europe , Humans , PolandABSTRACT
One of the most important advantages of mass spectrometry is the ability to quantify proteins and their modifications in parallel to obtain a holistic picture of the protein of interest. Here, we present a hybrid immunoaffinity targeted mass spectrometry (MS) method that combines efficient pan-antibody enrichment of a specific protein from plasma with the selectivity of high-resolution targeted MS analysis to quantitate specific proteoforms of interest. We used this approach to quantify plasma levels of the chemokine CXCL10 that has been associated with many immunological disorders such as systemic lupus erythematosus and primary Sjögren's Syndrome (pSS). The hybrid approach enabled sensitive, specific, and simultaneous quantification of total, full-length (active) CXCL101-77 and DPP4-truncated (inactive) CXCL103-77 in human plasma down to the low pg/mL level, reaching ELISA sensitivities. Samples from 30 control subjects and 34 pSS patients (n = 64) were analyzed. The ratio of CXCL101-77 to truncated CXCL103-77 was significantly increased in patients with pSS and provided the highest correlation with pSS disease activity. Therefore, this CXCL10 proteoform ratio represents an interesting exploratory disease activity biomarker to further investigate. As this strategy can be readily adapted to other plasma proteins and proteoforms of interest, we are convinced that it will lead to a more detailed understanding of proteoforms in physiology and pathology yielding more relevant biomarkers and drug targets.
Subject(s)
Lupus Erythematosus, Systemic , Sjogren's Syndrome , Biomarkers , Chemokine CXCL10/genetics , Enzyme-Linked Immunosorbent Assay , Humans , Mass Spectrometry , Sjogren's Syndrome/diagnosis , Sjogren's Syndrome/geneticsABSTRACT
OBJECTIVES: To determine the change in established biomarkers of cardiovascular (CV) risk, namely, total cholesterol/high-density lipoprotein cholesterol ratio (TC/HDL-C), N-terminal pro-brain natriuretic peptide (NT-proBNP) and insulin resistance (IR) in patients with early RA treated with two different treat-to-target strategies. METHODS: Fasting glucose, lipids, insulin and NT-proBNP were measured at baseline, weeks 26 and 78 in 79 DMARD-naïve RA patients, free of CV disease, as part of a double-blind randomized controlled trial of MTX with either infliximab (IFX) or methylprednisolone as induction therapy. Homeostasis model assessment-estimated IR (HOMA-IR) (glucose*insulin/405) was used to measure IR. Multiple imputation was employed, and linear regression analyses were adjusted for baseline values. RESULTS: Changes in DAS44-CRP did not differ between the treatment arms at weeks 26 and 78. Mean TC/HDL-C, HOMA-IR and NT-proBNP improved in both groups at weeks 26 and 78, although change in NT-proBNP was not statistically significant at week 78. Changes in TC/HDL-C and NT-proBNP were similar between treatment arms, but HOMA-IR values in the IFX + MTX arm were 42% lower than those treated with MTX + methylprednisolone at week 78 (P = 0.003); the difference remained significant after adjustment for baseline BMI, ACPA positivity, smoking status and intramuscular glucocorticoid use (P = 0.007). CONCLUSION: When implementing a treat-to-target approach, treatment of early RA was associated with improvement in TC/HDL-C, HOMA-IR and NT-proBNP, and a greater long-term improvement in HOMA-IR was seen in those treated with IFX. TRIAL REGISTRATION: EU Clinical Trials Register, http://www.clinicaltrialsregister.eu, Eudract-2005-005013-37; ISRTCNregisrty, http://www.isrctn.com, ISRCTN48638981.
Subject(s)
Antirheumatic Agents/therapeutic use , Arthritis, Rheumatoid/drug therapy , Infliximab/therapeutic use , Insulin Resistance/physiology , Methotrexate/therapeutic use , Adult , Aftercare , Aged , Biomarkers/metabolism , Blood Glucose/drug effects , Blood Glucose/metabolism , Cardiovascular Diseases/diagnosis , Cardiovascular Diseases/etiology , Cholesterol, HDL/metabolism , Diabetes Complications/complications , Double-Blind Method , Early Diagnosis , Female , Glucocorticoids/therapeutic use , Humans , Insulin/metabolism , Lipid Metabolism/drug effects , Male , Methylprednisolone/therapeutic use , Middle Aged , Natriuretic Peptide, Brain/metabolism , Peptide Fragments/metabolism , Risk Factors , Surveys and Questionnaires , Treatment Outcome , Young AdultSubject(s)
Antirheumatic Agents/therapeutic use , Arthritis, Rheumatoid/drug therapy , Cardiovascular Diseases/prevention & control , Adult , Aged , Arthritis, Rheumatoid/complications , Biomarkers/blood , Cardiovascular Diseases/etiology , Drug Therapy, Combination , Early Diagnosis , Female , Follow-Up Studies , Humans , Infliximab/therapeutic use , Male , Methotrexate/therapeutic use , Methylprednisolone/therapeutic use , Middle AgedABSTRACT
Data practices in biomedical research often rely on standards that build on normative assumptions regarding privacy and involve 'ethics work.' In an increasingly datafied research environment, identifiability gains a new temporal and spatial dimension, especially in regard to genomic data. In this paper, we analyze how genomic identifiability is considered as a specific data issue in a recent controversial case: publication of the genome sequence of the HeLa cell line. Considering developments in the sociotechnological and data environment, such as big data, biomedical, recreational, and research uses of genomics, our analysis highlights what it means to be (re-)identifiable in the postgenomic era. By showing how the risk of genomic identifiability is not a specificity of the HeLa controversy, but rather a systematic data issue, we argue that a new conceptualization is needed. With the notion of post-identifiability as a sociotechnological situation, we show how past assumptions and ideas about future possibilities come together in the case of genomic identifiability. We conclude by discussing how kinship, temporality, and openness are subject to renewed negotiations along with the changing understandings and expectations of identifiability and status of genomic data.
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Introduction: Population biobanks are essential for the development of public health screening and improvement of personalized medicine. Since 2012, Biobank of Lukasiewicz Research Network - PORT Polish Center for Technology Development (PORT Biobank) has collected more than 120 000 biological samples from nearly 5000 inhabitants of Lower Silesia, together with a variety of demographic, anthropometric, life style and health information. Material and methods: The analyzed group consisted of 2274 participants (1398 women, 876 men). Both women and men were further subdivided into five age decades (20+, 30+, 40+, 50+, 60+). For this study, the level of lipids (total cholesterol, high-density lipoprotein (HDL), low-density lipoprotein (LDL), triglycerides) was estimated and correlated with the level of high-sensitivity C-reactive protein (hs-CRP) and biometric parameters. Results: We have demonstrated for the first time that biochemical changes that may lead to cardiovascular diseases (CVD) occurred already in the group of people aged 30+. Our observation is based on measurements of lipids, glucose, inflammatory (hs-CRP) and biometric markers such as body mass index (BMI) and waist-to-hip ratio (WHR). Conclusions: Positive correlations with age for these variables suggest the ongoing progress of metabolic changes, which in the end may lead to a fatal outcome such as myocardial infarction or stroke. It suggests that CVD screening programs should be dedicated to a wider group, especially younger citizens, in order to prevent fatal outcomes related to CVD.
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The development of metabolomics in clinical applications has been limited by the lack of validation in large multicenter studies. Large population cohorts and their biobanks are a valuable resource for acquiring insights into molecular disease mechanisms. Nevertheless, most of their collections are not tailored for metabolomics and have been created without specific attention to the pre-analytical requirements for high-quality metabolome assessment. Thus, comparing samples obtained by different pre-analytical procedures remains a major challenge. Here, 1H NMR-based analyses are used to demonstrate how human serum and plasma samples collected with different operating procedures within several large European cohort studies from the Biobanking and Biomolecular Resources Infrastructure - Large Prospective Cohorts (BBMRI-LPC) consortium can be easily revealed by supervised multivariate statistical analyses at the initial stages of the process, to avoid biases in the downstream analysis. The inter-biobank differences are discussed in terms of deviations from the validated CEN/TS 16945:2016 / ISO 23118:2021 norms. It clearly emerges that biobanks must adhere to the evidence-based guidelines in order to support wider-scale application of metabolomics in biomedicine, and that NMR spectroscopy is informative in comparing the quality of different sample sources in multi cohort/center studies.
Subject(s)
Biological Specimen Banks , Metabolomics , Humans , Magnetic Resonance Spectroscopy , Metabolomics/methods , Prospective Studies , SerumABSTRACT
Personalised medicine (PM) presents a great opportunity to improve the future of individualised healthcare. Recent advances in -omics technologies have led to unprecedented efforts characterising the biology and molecular mechanisms that underlie the development and progression of a wide array of complex human diseases, supporting further development of PM. This article reflects the outcome of the 2021 EATRIS-Plus Multi-omics Stakeholder Group workshop organised to 1) outline a global overview of common promises and challenges that key European stakeholders are facing in the field of multi-omics research, 2) assess the potential of new technologies, such as artificial intelligence (AI), and 3) establish an initial dialogue between key initiatives in this space. Our focus is on the alignment of agendas of European initiatives in multi-omics research and the centrality of patients in designing solutions that have the potential to advance PM in long-term healthcare strategies.
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In the past decade, there has been a surge of interest in the examination of cardiovascular (CV) outcomes in RA, where it is widely accepted that there is an enhanced risk of CV disease (CVD). In recent years, a number of novel soluble biomarkers of CV risk have been examined in the general population to investigate whether any value is added to the routine measurement of traditional (Framingham) CV risk factors. We briefly review these novel markers and identify those markers that appear distinct to systemic inflammation, which may then be applicable to evaluation in patients with RA. We then investigate whether any of the soluble CV biomarkers provide additional information on the risk of developing subclinical CVD or cardiac events in an individual patient with RA, or whether they may only provide a surrogate measure of the systemic inflammatory load experienced by such patients.
Subject(s)
Arthritis, Rheumatoid/metabolism , Biomarkers/metabolism , Cardiovascular Diseases/metabolism , Inflammation/metabolism , Arthritis, Rheumatoid/diagnosis , Arthritis, Rheumatoid/epidemiology , Cardiovascular Diseases/diagnosis , Cardiovascular Diseases/epidemiology , Comorbidity , Epidemiologic Methods , Humans , Inflammation/diagnosis , Risk Factors , Seroepidemiologic Studies , United Kingdom/epidemiologyABSTRACT
Biobanks act as the custodians for the access to and responsible use of human biological samples and related data that have been generously donated by individuals to serve the public interest and scientific advances in the health research realm. Risk assessment has become a daily practice for biobanks and has been discussed from different perspectives. This paper aims to provide a literature review on risk assessment in order to put together a comprehensive typology of diverse risks biobanks could potentially face. Methodologically set as a typology, the conceptual approach used in this paper is based on the interdisciplinary analysis of scientific literature, the relevant ethical and legal instruments and practices in biobanking to identify how risks are assessed, considered and mitigated. Through an interdisciplinary mapping exercise, we have produced a typology of potential risks in biobanking, taking into consideration the perspectives of different stakeholders, such as institutional actors and publics, including participants and representative organizations. With this approach, we have identified the following risk types: economic, infrastructural, institutional, research community risks and participant's risks. The paper concludes by highlighting the necessity of an adaptive risk governance as an integral part of good governance in biobanking. In this regard, it contributes to sustainability in biobanking by assisting in the design of relevant risk management practices, where they are not already in place or require an update. The typology is intended to be useful from the early stages of establishing such a complex and multileveled biomedical infrastructure as well as to provide a catalogue of risks for improving the risk management practices already in place.
Subject(s)
Biological Specimen Banks , Publications , Humans , Risk ManagementABSTRACT
Cardiac hypertrophy is associated with a dramatic change in the gene expression profile of cardiac myocytes. Many genes important during development of the fetal heart but repressed in the adult tissue are reexpressed, resulting in gross physiological changes that lead to arrhythmias, cardiac failure, and sudden death. One transcription factor thought to be important in repressing the expression of fetal genes in the adult heart is the transcriptional repressor REST (repressor element 1-silencing transcription factor). Although REST has been shown to repress several fetal cardiac genes and inhibition of REST function is sufficient to induce cardiac hypertrophy, the molecular mechanisms employed in this repression are not known. Here we show that continued REST expression prevents increases in the levels of the BNP (Nppb) and ANP (Nppa) genes, encoding brain and atrial natriuretic peptides, in adult rat ventricular myocytes in response to endothelin-1 and that inhibition of REST results in increased expression of these genes in H9c2 cells. Increased expression of Nppb and Nppa correlates with increased histone H4 acetylation and histone H3 lysine 4 methylation of promoter-proximal regions of these genes. Furthermore, using deletions of individual REST repression domains, we show that the combined activities of two domains of REST are required to efficiently repress transcription of the Nppb gene; however, a single repression domain is sufficient to repress the Nppa gene. These data provide some of the first insights into the molecular mechanism that may be important for the changes in gene expression profile seen in cardiac hypertrophy.
Subject(s)
Chromatin/metabolism , DNA-Binding Proteins/metabolism , Gene Expression Regulation , Heart/physiology , Nerve Tissue Proteins/metabolism , Repressor Proteins/metabolism , Animals , Atrial Natriuretic Factor/genetics , Atrial Natriuretic Factor/metabolism , Cardiomegaly/genetics , Cells, Cultured , Co-Repressor Proteins , DNA-Binding Proteins/genetics , Endothelin-1/metabolism , Guanylate Cyclase/genetics , Guanylate Cyclase/metabolism , Heart Ventricles/cytology , Histones/metabolism , Humans , Macromolecular Substances , Male , Myocytes, Cardiac/cytology , Myocytes, Cardiac/physiology , Nerve Tissue Proteins/genetics , Rats , Rats, Wistar , Receptors, Atrial Natriuretic Factor/genetics , Receptors, Atrial Natriuretic Factor/metabolism , Repressor Proteins/genetics , Transcription, GeneticABSTRACT
During the COVID-19 pandemic, the European biobanking infrastructure is in a unique position to preserve valuable biological material complemented with detailed data for future research purposes. Biobanks can be either integrated into healthcare, where preservation of the biological material is a fork in clinical routine diagnostics and medical treatment processes or they can also host prospective cohorts or material related to clinical trials. The paper discussed objectives of BBMRI-ERIC, the European research infrastructure established to facilitate access to quality-defined biological materials and data for research purposes, with respect to the COVID-19 crisis: (a) to collect information on available European as well as non-European COVID-19-relevant biobanking resources in BBMRI-ERIC Directory and to facilitate access to these via BBMRI-ERIC Negotiator platform; (b) to help harmonizing guidelines on how data and biological material is to be collected to maximize utility for future research, including large-scale data processing in artificial intelligence, by participating in activities such as COVID-19 Host Genetics Initiative; (c) to minimize risks for all involved parties dealing with (potentially) infectious material by developing recommendations and guidelines; (d) to provide a European-wide platform of exchange in relation to ethical, legal, and societal issues (ELSI) specific to the collection of biological material and data during the COVID-19 pandemic.
Subject(s)
Betacoronavirus/pathogenicity , Biomedical Research/organization & administration , Coronavirus Infections/epidemiology , Information Dissemination/methods , International Cooperation/legislation & jurisprudence , Pandemics , Pneumonia, Viral/epidemiology , Antiviral Agents/therapeutic use , Artificial Intelligence , Betacoronavirus/drug effects , Betacoronavirus/genetics , Biological Specimen Banks/supply & distribution , COVID-19 , Clinical Trials as Topic , Coronavirus Infections/diagnosis , Coronavirus Infections/drug therapy , Coronavirus Infections/genetics , Datasets as Topic , Europe/epidemiology , Humans , Information Dissemination/ethics , Pneumonia, Viral/diagnosis , Pneumonia, Viral/drug therapy , Pneumonia, Viral/genetics , Practice Guidelines as Topic , Public Health/economics , SARS-CoV-2ABSTRACT
Many types of biomedical research projects depend on high-quality biological material with a data set attached. The Quality Management System (QMS) is focused on operational standards for all organizational activities to ensure that the described quality of each procedure, product, or service is guaranteed. The implementation of the QMS is necessary for the provision of both high quality and repeatability of processes in research laboratories. The current status of implementation of the QMS is determined according to the "Organisation of Polish Biobanking Network" within the project "Biobanking and Biomolecular Resources Research Infrastructure BBMRI-ERIC" supported by the Polish Ministry of Science and Higher Education-decision number DIR/WK/2017/01. According to the above, preliminary audits in six Polish institutions were conducted and reports with recommendations concerning the implementation and improvement of the QMS in Polish biobanks were prepared. During all audits, 13 QMS main areas were analyzed. All audited units belong to the BBMRI.pl consortium, which is responsible for the creation of the Polish Biobanking Network within the BBMRI-ERIC structure. Among all 13 analyzed areas, 27 deviations were identified. Eleven of them were implemented in all audited biobanks but defined as the areas for improvement, 16 of them were not implemented correctly or not implemented at all, respectively (areas underlined to corrective procedures).
Subject(s)
Biological Specimen Banks/standards , Information Dissemination/methods , Biological Specimen Banks/organization & administration , Biomedical Research/standards , Databases, Factual , Guidelines as Topic , Humans , PolandABSTRACT
Cyclic AMP exhibits local (sarcolemmal) and global (cytosolic) patterns of signalling, allowing receptor-specific signals to be generated by a single second messenger. Here we determine whether caveolae, invaginated lipid rafts, are responsible for confining the beta(2) adrenoceptor (AR) cAMP signal to the sarcolemmal compartment. Myocytes were treated with the cholesterol-depleting agent methyl-beta-cyclodextrin (M beta C) to disrupt caveolae. Caveolae-containing membrane fractions were isolated by detergent-free sucrose gradient fractionation. Cell shortening and phosphorylation of the sarcoplasmic reticular protein phospholamban (PLB) and the myofilament protein troponin I (TnI) were measured in response to beta(2) AR stimulation (with salbutamol in the presence of 1 microM atenolol). Ser(16) phosphorylation of PLB (pPLB), Ser(22,23) phosphorylation of TnI (pTnI), and positive lusitropy were used as indices of global cAMP signals. The ability of M beta C to disrupt caveolae was confirmed by selective depletion of the buoyant membrane fractions of cholesterol and caveolin 3, the 2 essential components of caveolae. In control cells, no change in pPLB, pTnI or time to half relaxation was recorded with beta(2) AR stimulation (P>0.05), but following caveolar disruption a 60-70% increase in phosphorylation of both proteins was seen, accompanied by positive lusitropy (P<0.05). These data show for the first time that disrupting caveolae converts the sarcolemmal-confined cAMP signal associated with beta(2) AR stimulation to a global signal that targets proteins of the sarcoplasmic reticulum and myofilaments, with functional sequelae. The role of caveolae in spatial control of cAMP may be relevant to perturbation of beta AR signalling in cardiovascular disease.
Subject(s)
Caveolae/metabolism , Cyclic AMP/metabolism , Myocytes, Cardiac/metabolism , Receptors, Adrenergic, beta-2/metabolism , Sarcolemma/metabolism , Second Messenger Systems , Actin Cytoskeleton/metabolism , Adrenergic beta-2 Receptor Agonists , Adrenergic beta-Agonists/pharmacology , Albuterol/pharmacology , Animals , Atenolol/pharmacology , Calcium-Binding Proteins/metabolism , Cardiovascular Diseases/metabolism , Caveolin 2/metabolism , Caveolin 3/metabolism , Cholesterol/metabolism , Cytosol , Male , Phosphorylation/drug effects , Rats , Rats, Wistar , Sarcoplasmic Reticulum/metabolism , Second Messenger Systems/drug effects , Troponin I/metabolismABSTRACT
The known challenge of underutilization of data and biological material from biorepositories as potential resources for medical research has been the focus of discussion for over a decade. Recently developed guidelines for improved data availability and reusability-entitled FAIR Principles (Findability, Accessibility, Interoperability, and Reusability)-are likely to address only parts of the problem. In this article, we argue that biological material and data should be viewed as a unified resource. This approach would facilitate access to complete provenance information, which is a prerequisite for reproducibility and meaningful integration of the data. A unified view also allows for optimization of long-term storage strategies, as demonstrated in the case of biobanks. We propose an extension of the FAIR Principles to include the following additional components: (1) quality aspects related to research reproducibility and meaningful reuse of the data, (2) incentives to stimulate effective enrichment of data sets and biological material collections and its reuse on all levels, and (3) privacy-respecting approaches for working with the human material and data. These FAIR-Health principles should then be applied to both the biological material and data. We also propose the development of common guidelines for cloud architectures, due to the unprecedented growth of volume and breadth of medical data generation, as well as the associated need to process the data efficiently.
Subject(s)
Biological Specimen Banks , Confidentiality/standards , Databases, Factual/standards , Information Dissemination/methods , Biological Specimen Banks/organization & administration , Biological Specimen Banks/standards , Guidelines as Topic , HumansABSTRACT
In Poland storage of human biological samples takes place at most universities and scientific institutions conducting research projects in the field of biomedicine. The First International Biobanking Conference organized by the Ministry of Science and Higher Education in 2014 shed a light on the situation of Polish biobanking infrastructures. The country has around 40 large biorepositories, which store unique biological material such as whole brains, muscle fibers from patients with rare diseases, as well as thousands of samples from patients with lifestyle diseases. There are only two population-based biobanks working locally and several disease-oriented biobanks specializing mainly in oncological diseases. Consortium BBMRI.pl created plans for establishing a Polish Network of Biobanks, with national node which meets standards for biobanks and cooperation to guarantee development of biomedical sciences and international collaboration between Poland and other countries. The Polish network will enhance research activities, due to better visibility of samples and data that are stored in the national biobanking catalogue. However, it requires more than a comprehensive understanding of all benefits. The list of examples of benefits can be presented as follows: (i) a reduction of the duration and cost of clinical trials and subsequent time to market for anticancer drugs; (ii) more precise patient diagnosis and the associated impact on treatment and lower healthcare costs for providers, individuals, and the nation; (iii) improvements in research experiment time frames and data efficiencies; (iv) convergence to an industry standards for biospecimen quality; (v) optimization of capital infrastructure and IT technology.
Subject(s)
Biological Specimen Banks/organization & administration , Biological Specimen Banks/economics , Biological Specimen Banks/standards , Biomedical Research/economics , Biomedical Research/standards , Humans , PolandABSTRACT
A calculation grid developed by an international expert group was tested across biobanks in six countries to evaluate costs for collections of various types of biospecimens. The assessment yielded a tool for setting specimen-access prices that were transparently related to biobank costs, and the tool was applied across three models of collaborative partnership.
Subject(s)
Biomedical Research/economics , Commerce/economics , Specimen Handling/economics , Tissue Banks/economics , Biomedical Research/organization & administration , Budgets , Commerce/organization & administration , Cooperative Behavior , Cost-Benefit Analysis , Europe , Humans , Models, Economic , Models, Organizational , Tissue Banks/organization & administration , WorkflowABSTRACT
BACKGROUND: Many ion channels are preferentially located in caveolae where compartmentalisation/scaffolding with signal transduction components regulates their activity. Channels that are mechanosensitive may be additionally dependent on caveolar control of the mechanical state of the membrane. Here we test which mechanism underlies caveolar-regulation of the mechanosensitive I(Cl,swell) channel in the adult cardiac myocyte. METHODOLOGY/PRINCIPAL FINDINGS: Rat ventricular myocytes were exposed to solution of 0.02 tonicity (T; until lysis), 0.64T for 10-15 min (swelling), and/or methyl-beta-cyclodextrin (MBCD; to disrupt caveolae). MBCD and 0.64T swelling reduced the number of caveolae visualised by electron microscopy by 75 and 50% respectively. MBCD stimulated translocation of caveolin 3 from caveolae-enriched buoyant membrane fractions, but both caveolin 1 and 3 remained in buoyant fractions after swelling. I(Cl,swell) inhibition in control cells decreased time to half-maximal volume (t(0.5,vol); 0.64T), consistent with a role for I(Cl,swell) in volume regulation. MBCD-treated cells showed reduced time to lysis (0.02T) and t(0.5,vol) (0.64T) compared with controls. The negative inotropic response to swelling (an index of I(Cl,swell) activation) was enhanced by MBCD. CONCLUSIONS/SIGNIFICANCE: These data show that disrupting caveolae removes essential membrane reserves, which speeds swelling in hyposmotic conditions, and thereby promotes activation of I(Cl,swell). They illustrate a general principle whereby caveolae as a membrane reserve limit increases in membrane tension during stretch/swelling thereby restricting mechanosensitive channel activation.