Ethics guidelines for research with the recently dead

Pentz, Rebecca D.; Cohen, Cynthia B.; Wicclair, Mark R.; DeVita, Michael A.; Flamm, Anne L.; Youngner, Stuart J.; Hamric, Ann B.; McCabe, Mary S.; Glover, Jacqueline J.; Kittiko, Winona J.; Kinlaw, Kathy; Keller, James W.; Asch, Adrienne; Kavanagh, John J.; Arap, Wadih

doi:10.1038/nm1105-1145

Cited by 96 publications

(59 citation statements)

References 34 publications

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“…We adapted the next-generation pyrosequencing methodology (454/Roche) for phage DNA; for proof-of-principle, we used tissues obtained after intravenous administration of a phage library to end-of-life patients [18]–[20]. To determine the capacity of this approach for the high-throughput generation of phage sequences, we produced insert-containing amplicons from surgical biopsies of four human tissues (skin, white adipose tissue, bone marrow, and skeletal muscle), with oligonucleotides flanking the DNA insert coding for the peptide in the pIII gene (Fig.…”

Section: Resultsmentioning

confidence: 99%

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Next-Generation Phage Display: Integrating and Comparing Available Molecular Tools to Enable Cost-Effective High-Throughput Analysis

et al. 2009

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BackgroundCombinatorial phage display has been used in the last 20 years in the identification of protein-ligands and protein-protein interactions, uncovering relevant molecular recognition events. Rate-limiting steps of combinatorial phage display library selection are (i) the counting of transducing units and (ii) the sequencing of the encoded displayed ligands. Here, we adapted emerging genomic technologies to minimize such challenges.Methodology/Principal FindingsWe gained efficiency by applying in tandem real-time PCR for rapid quantification to enable bacteria-free phage display library screening, and added phage DNA next-generation sequencing for large-scale ligand analysis, reporting a fully integrated set of high-throughput quantitative and analytical tools. The approach is far less labor-intensive and allows rigorous quantification; for medical applications, including selections in patients, it also represents an advance for quantitative distribution analysis and ligand identification of hundreds of thousands of targeted particles from patient-derived biopsy or autopsy in a longer timeframe post library administration. Additional advantages over current methods include increased sensitivity, less variability, enhanced linearity, scalability, and accuracy at much lower cost. Sequences obtained by qPhage plus pyrosequencing were similar to a dataset produced from conventional Sanger-sequenced transducing-units (TU), with no biases due to GC content, codon usage, and amino acid or peptide frequency. These tools allow phage display selection and ligand analysis at >1,000-fold faster rate, and reduce costs ∼250-fold for generating 106 ligand sequences.Conclusions/SignificanceOur analyses demonstrates that whereas this approach correlates with the traditional colony-counting, it is also capable of a much larger sampling, allowing a faster, less expensive, more accurate and consistent analysis of phage enrichment. Overall, qPhage plus pyrosequencing is superior to TU-counting plus Sanger sequencing and is proposed as the method of choice over a broad range of phage display applications in vitro, in cells, and in vivo.

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Section: Resultsmentioning

confidence: 99%

“…This study design was reviewed and approved by the Institutional Review Board of the University of Texas M. D. Anderson Cancer Center and followed a pre-established ethics framework [18]–[19].…”

Section: Methodsmentioning

confidence: 99%

Next-Generation Phage Display: Integrating and Comparing Available Molecular Tools to Enable Cost-Effective High-Throughput Analysis

et al. 2009

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“…In vivo phage display is one approach that can potentially identify and validate functional ligand-mimics binding to relevant membrane receptors that promote cell internalization within the context of the tumor microenvironment. Our group has pioneered the direct screening of phage display random peptide libraries in cancer patients to enable unbiased discovery of tumor targets (5–6). In previous work with this platform technology, we isolated a ligand that mimics interleukin-11 (IL-11) motif (cyclic peptide CGRRAGGSC) and have demonstrated that the interleukin-11 receptor (IL-11R) is a tumor target in primary tumors of bone, such as osteosarcoma, and in secondary bone metastases from solid tumors such as prostate cancer (7–10).…”

Section: Introductionmentioning

confidence: 99%

Targeting IL11 Receptor in Leukemia and Lymphoma: A Functional Ligand-Directed Study and Hematopathology Analysis of Patient-Derived Specimens

Karjalainen

Jaalouk

Bueso‐Ramos

et al. 2015

Clinical Cancer Research

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Purpose The interleukin-11 receptor (IL-11R) is an established molecular target in primary tumors of bone, such as osteosarcoma, and in secondary bone metastases from solid tumors such as prostate cancer. However, its potential role in management of hematopoietic malignancies has not yet been determined. Here we evaluated the IL-11R as a candidate therapeutic target in human leukemia and lymphoma. Experimental Design and Results First, we show that the IL-11R protein is expressed in a variety of human leukemia- and lymphoma derived cell lines and in a large panel of bone marrow samples from leukemia and lymphoma patients, while expression is absent from non-malignant control bone marrow. Moreover, a targeted peptidomimetic prototype (termed BMTP-11) specifically bound to leukemia and lymphoma cell membranes, induced ligand-receptor internalization mediated by the IL-11R, and resulted in a specific dose-dependent cell death induction in these cells. Finally, a pilot drug lead-optimization program yielded a new myristoylated BMTP-11 analog with an apparent improved anti-leukemia cell profile. Conclusion These results indicate (i) that the IL-11R is a suitable cell surface target for ligand-directed applications in human leukemia and lymphoma and (ii) that BMTP-11 and its derivatives have translational potential against this group of malignant diseases.

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“…(9) Although guidelines have been proposed for interventional research on the dying(10,11) and non-interventional research on the recently dead,(12,13) the requirements for informed consent from potential donors, recipients, or both remain uncertain in the specific context of deceased donor management research. In this essay, we explore when, how, and from whom consent should be sought for research on brain-dead potential donors after neurological determination of death (DNDD), also known as brain-dead donors.…”

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confidence: 99%

Informed consent in research to improve the number and quality of deceased donor organs*

Rey

Ware

Matthay

et al. 2011

Critical Care Medicine

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Improving the management of potential organ donors in the ICU could meet an important public health goal by increasing the number and quality of transplantable organs. However, randomized clinical trials (RCTs) are needed to quantify the extent to which specific interventions might enhance organ recovery and outcomes among transplant recipients. Among several barriers to conducting such studies are the absence of guidelines for obtaining informed consent for such studies, and the fact that deceased organ donors are not covered by extant federal regulations governing oversight of research with human subjects. This paper explores the underexamined ethical issues that arise in the context of donor management studies, and provides ethical guidelines and suggested regulatory oversight mechanisms to enable such studies to be conducted ethically. We conclude that both the respect that is traditionally accorded to the prior wishes of the dead and the possibility of post-mortem harm support a role for surrogate consent of donors in such RCTs. Furthermore, although recipients will often be considered human subjects under federal regulations, several ethical arguments support waiving requirements for recipient consent in donor management RCTs. Finally, we suggest that new regulatory mechanisms, perhaps linked to existing regional and national organ donation and transplantation infrastructures, must be established to protect patients in donor management studies while limiting unnecessary barriers to the conduct of this important research.

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Ethics guidelines for research with the recently dead

Cited by 96 publications

References 34 publications

Next-Generation Phage Display: Integrating and Comparing Available Molecular Tools to Enable Cost-Effective High-Throughput Analysis

Next-Generation Phage Display: Integrating and Comparing Available Molecular Tools to Enable Cost-Effective High-Throughput Analysis

Targeting IL11 Receptor in Leukemia and Lymphoma: A Functional Ligand-Directed Study and Hematopathology Analysis of Patient-Derived Specimens

Informed consent in research to improve the number and quality of deceased donor organs*

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