Research on Human-animal Entities: Ethical and Regulatory Aspects in Europe

To review the ethical and regulatory issues related to the research on human-animal entities at various stages. Review of scientific publications, laws and ethical guidelines in this field up through September 2008. The article presents the overall picture of the research on human-animal entities in Europe, including the public opinion and the country-specific regulations and guidelines regarding such research, discusses the ethical issues, including both arguments opposing and favoring such research, as well as discusses and clarifies the terminology used. Creation of human-animal entities with the potential for what may be viewed as human faculties raises profound questions concerning the rights and responsibilities of human beings. There is great need for informed discussions and interchanges between the expert researchers, ethicists, policymakers, lawyers and the public in general to come to consensus regarding the issues discussed in this paper. Suggestions regarding these rights and responsibilities are overviewed.     

Policy Interoperability in Stem Cell Research: Demystifying Harmonization

Scientific developments in the field of stem cell research continue to emerge at incredible speed and so too has the contentious debate surrounding their broad implications. Though economic, socio-ethical and legal concerns remain, at both national and international forums; we are witnessing a departure from an “embryo-centric” approach, to one that is focused on the globalization of research and to the ensuing need for policy interoperability. The common response to the challenges associated with the meaning, scope, and ethical significance of variance in national policies, is a call for the creation of uniform legal and ethical standards. However, this call towards policy convergence on the fundamental ethical and governance principles underpinning policies choices has led to confusion and to the mystification of the notion of harmonization. In this article we aim demystify the notion of policy harmonization in the context of stem cell research. We will do so by surveying the diverse elements to be harmonized. We will then present the problems of policy interoperability in the context of the globalization of SC research, in order to propose that the goal of harmonization in this field lies in the identification of prospective strategies to foster seamless cross-jurisdictional collaboration. Finally, policy interoperability will be analyzed through the lens of a range of policy approaches addressing the cross-jurisdictional transfer of hESC lines with the aim of demonstrating that the apparent ethical-political-legal divide in some contexts largely vanishes once we grasp the notion of harmonization and identify points of convergence.

Hematopoietic Stem Cell Aging: Wrinkles In Stem Cell Potential

Hematopoietic stem cells (HSC) continuously replenish the blood and immune systems. Their activity must be sustained throughout life to support optimal immune responses. It has been thought that stem cells may be somewhat protected from age because of their perpetual requirement to replenish the blood, however studies over the past 10 years have revealed dramatic changes in HSC function and phenotype with respect to age. When the number of HSC within murine bone marrow is measured, an increase in concentration and absolute number of HSC within the bone marrow is observed as the animal ages, paralleled with increased homogeneity of stem cell marker expression. Results from transplantation studies demonstrate that although there is a decline in hematopoietic output on a per-cell basis, the increase in number provides sufficient, yet abnormal, blood production throughout the lifespan of the animal. HSC may play a role in immunosenescence through cell-fate decisions leading to an overproduction of myeloid cells and an underproduction of lymphocytes. When examining gene expression of aged HSC, recent studies have highlighted several key factors contributing to increased inflammation, stress response and genomic instability. Here, we will review the general phenotype observed with aging of the hematopoietic system, focusing on the HSC, and compile recent expression profiling efforts that have examined HSC aging. Electronic supplementary material The online version of this article (doi:) contains supplementary material, which is available to authorized users.     

Stem Cell Chronicles: Autobiographies Within Genomes

Human stem cell studies are difficult because many of the powerful experimental approaches that mark and follow stem cells and their progeny are impractical. Moreover, humans are long-lived, and it would literally take a lifetime to follow stem cell fates prospectively. Considering these hurdles, an ideal method would not require prior experimental manipulations but still allow “observations” of human stem cells from birth to death. The purpose of this review is to outline how histories or fates are likely to be surreptitiously recorded within somatic cell genomes by replication errors (molecular clock hypothesis). It may be possible to reconstruct stem cell lifetimes by measuring the random somatic changes that accumulate within their genomes, or the genomes of their more-easy-to-identify progeny.     

Cross-border Research on Human Embryonic Stem Cells: Legal and Ethical Considerations

Although stem cell research is a field that stands to benefit a lot from international cooperation, collaboration between scientists of different countries is hampered by the great divergence in national stem cell legislations. More specifically, researchers from countries with restrictive stem cell policies find themselves unable to participate in international research or attend meetings or workshops in more permissive environments as they fear being prosecuted in their home country for activities that are deemed acceptable abroad. Juridical clarity on this subject is long overdue. Legally, extraterritorial jurisdiction based on the nationality principle does not conflict with international law. However, invoking this principle to prosecute stem cell researchers would constitute a breach with the current custom to limit extraterritorial jurisdiction to exceptional crimes or circumstances. On the ethical front, legislators have an obligation towards their constituents to protect them from harm through the criminal justice system, but at the same time they should be wary of legal moralism and of jeopardising freedom of research. Researchers on their part cannot simply ignore the law whenever it deviates from their personal moral opinions, but they are not acting unethically if they perform research that they esteem to be ethically justified where it is also legally accepted. Allowing researchers to work freely abroad—within the jurisdiction of the host country—is a way for legislator and researcher to show respect for each other’s different moral values and to balance their rights and obligations towards each other.     

干细胞文献汇总分析

目的 干细胞技术已越来越多地用于不同疾病的治疗,但其疗效及安全性仍未得到充分证实。本文旨在全面分析干细胞领域文献的发表现状,以期为干细胞治疗的选择提供一定参考。方法 通过检索CNKI中文数据库及Web of Science英文数据库中关于干细胞相关的文献。按照不同年代、学科分类、基金来源、机构,统计文献数量。结果 CNKI及Web of Science数据库分别检索到242613篇及438585篇有关干细胞的文献。根据年代,文献发表数量呈递增趋势。CNKI中文数据库中,国内发表文献数量最多的学科为基础医学,国内资助发表最多文献的基金是国家自然科学基金,国内发表文献数量最多的机构是第四军医大学（空军军医大学）。Web of Science数据库中,国际上发表文献数量最多的学科为血液学,国际上发表文献数量最多的机构是美国加州大学。结论 干细胞已受到了越来越多的基础科学研究者以及不同临床学科医师们的关注。国内仍以基础研究为主,未来需在不同临床学科开展更多高质量临床研究,提供高级别证据指导临床实践。     

Stem Cell Transplantation and Informatics: Current Considerations

Informatics strategies and applications available to stem cell transplant (SCT) programs are diverse and changing rapidly. Although most hospitals have electronic medical records (EMRs), few are equipped with specialized SCT applications. Most EMRs do not contain critical elements to support SCT practice and research. Strategies to optimize information technology resources to support SCT programs are reviewed and technical and workflow support discussed. Guidance and rationale for the use of both SCT applications and EMRs are emphasized.     

Diversity in Public Views Toward Stem Cell Sources and Policies

Studies of public views on stem cell research have traditionally focused on human embryonic stem cells. With more recent scientific research on developing other stem cell sources, a series of focus group studies was undertaken with Canadian adults to examine their views on different stem cell sources (adult, umbilical cord blood, human embryonic stem cells, somatic cell nuclear transfer or SCNT, and interspecies nuclear transfer, or iSCNT). Views on three different policy models—a permissive, middle-of-the-road and restrictive policy approach—were also explored. Participants were recruited from several different social groups including patients, young adults, seniors, members of two ethnic communities, and a mixed group of adults. Participants were generally supportive of the use of adult stem cell sources. While there was also majority support for the use of hESC and SCNT, this was conditional on strict regulatory oversight. There was also majority support for a permissive policy which allows research on hESC and SCNT. General themes that cut across different groups included the potential cost of new technologies to the health care system, issues around who would gain access to these technologies, and trust in the scientific establishment and regulatory systems. A diversity of viewpoints was found as participants justified their positions on stem cell sources and policy approaches, showing more complexity and nuance than has been generally portrayed. The authors acknowledge support for this study from the project “Towards the clinic: ethical, legal, and social issues relevant to emerging stem cell therapies” funded by the Stem Cell Network of Canada.     

Adjustment in Parents of Children Undergoing Stem Cell Transplantation

Pediatric stem cell transplantation (SCT) is a demanding procedure for children and parents. Interventions to promote positive adjustment of parents in this setting are needed. A total of 171 patient-parent dyads from 4 sites received 1 of 3 interventions to reduce SCT-related distress: a child intervention with massage and humor therapy, an identical child intervention plus a parent intervention with massage and relaxation/imagery, or standard care. Parents completed weekly self-report measures of distress and positive affect during the acute phase of treatment (weeks −1 through +6); and measures of depression, posttraumatic stress (PTSD), and benefit finding at baseline and week +24. No significant differences across treatment arms were observed on repeated measures of parental distress. There was a marginally significant effect of the child intervention on parental positive affect. Over time, parental distress decreased significantly and positive affect increased significantly in all groups. Similarly, there were no significant intervention effects on the global adjustment outcomes of depression, PTSD, and benefit finding. However, reports of depression and PTSD decreased significantly and reports of benefit finding increased significantly from baseline to week +24 for all groups. Across all study arms, parent adjustment improved over time, suggesting that parents demonstrate a transient period of moderately elevated distress at the time of their child's admission for transplantation, followed by rapid improved to normative levels of adjustment. Similar to results previously reported for their children, these parents appear resilient to the challenges of transplantation.     

Emerging Ethical, Legal and Social Issues Associated with Stem Cell Research & and the Current Role of the Moral Status of the Embryo

Since its early days, stem cell research, particularly human embryonic stem cell research, has been the focus of intense social debate, and the question of the moral status of the embryo has been a central issue in the controversy. Despite this friction, and while it has yet to obtain widespread success in clinical applications, stem cell research remains a great hope for future advances in healthcare. In this paper, we will discuss the results of our systematic literature review in which we examined recent social science, legal and biomedical discourse, as well as Canadian print media discourse, associated with stem cell research in order to assess the role the question of the moral status of the embryo currently plays in these forums, and to identify what other issues are emerging and receiving attention. This analysis will assist with recognizing the issues which are likely to inform future policy and will facilitate forecasting the probable direction of the continually developing social discourse surrounding stem cell research.

Hematopoietic Stem Cell Transplantation in Patients with Lymphomatoid Granulomatosis: A European Group for Blood and Marrow Transplantation Report

Lymphomatoid granulomatosis (LG) is a very rare, Epstein-Barr virus–associated lymphoproliferative disorder of B cells. Prognosis is poor, particularly after relapse and no curative treatment exists. We report the results of high-dose therapy and autologous stem cell transplantation (ASCT) or reduced-intensity conditioning and allogeneic stem cell transplantation (alloSCT) in patients with multiply relapsed LG. A European Group for Blood and Marrow Transplantation survey identified 10 patients who had received 9 ASCT and 4 alloSCT. All patients had active disease at the time of transplantation. With a median follow-up of 5.1 (range, 1.4 to 6.3) years, 6 patients are alive and disease-free. Two ASCT patients died of septicemia early after transplantation, and 1 committed suicide after being in continuous complete remission 19 months after ASCT. Another patient allografted 4 years after ASCT remained disease-free but died of severe graft-versus-host disease 3 months after alloSCT. High-dose therapy followed by ASCT and alloSCT are effective therapeutic options and should be considered in all patients with refractory and multiply relapsed LG.     

Familial Occurrence of Pulmonary Embolism after Intravenous,Adipose Tissue-Derived Stem Cell Therapy

The therapeutic potential of human multipotent mesenchymal stromal cells, especially human adipose tissue-derived stem cells (hASC), is promising. However, there are concerns about the safety of infusion of hASC in human. Recently, we have experienced pulmonary embolism and infarct among family members who have taken multiple infusions of intravenous autologous hASC therapy. A 41-year-old man presented with chest pain for one month. Chest CT showed multiple pulmonary artery embolism and infarct at right lung. Serum D-dimer was 0.8 µg/mL (normal; 0-0.5 µg/mL). He had received intravenous autologous adipose tissue-derived stem cell therapy for cervical herniated intervertebral disc three times (one, two, and three months prior to the visit). His parents also received the same therapy five times and their chest CT also showed multiple pulmonary embolism. These cases represent artificial pulmonary embolisms and infarct after IV injection of hASC. Follow-up chest CT showed spontaneous resolution of lesions in all three patients.     

经冠状动脉灌注不同类型的干细胞对慢性心功能不全兔心功能影响的比较研究

研究非选择性冠状动脉灌注移植干细胞治疗非缺血性心功能不全的可行性；比较自体骨髓单个核细胞（BMCs）、间充质干细胞（MSCs）和成肌细胞（SMs）移植对心功能的影响。使用阿霉素制作兔心功能不全模型，经双球囊封堵主动脉根部后分别灌注自体BMCs、MSCs、SMs和无血清DMEM。比较移植前后左室射血分数（LVEF）及左室舒张末期内径（LVED）变化。结果表明，干细胞移植术中及移植后4周内病死率为7．1％和16．7％。假手术组移植后LVEF有继续恶化的趋势（P〉0．05）。移植4周后，BMCs组LVEF明显改善（P〈0．05，n=8）；MSCs组LVEF有改善的趋势（P〉0．05，n=8）；SMs组LVEF未见改善（P〉0．05，n=6）。假手术组移植后LVED继续扩大（P〈0．05）；各移植组LVED有继续扩大的趋势（P〉0．05）。移植各组心肌组织切片上均发现了存活的移植细胞。移植的BMCs和MSCs表达了肌钙蛋白I。说明，经冠状动脉灌注细胞移植可用于治疗非缺血性心功能不全的实验研究。     

Cytogenetics,Donor Type,and Use of Hypomethylating Agents in Myelodysplastic Syndrome with Allogeneic Stem Cell Transplantation

We investigated the impact of patient and disease characteristics, including cytogenetics, previous therapy, and depth of response, on the outcome of allogeneic hematopoietic stem cell transplantation (HSCT) for patients with myelodysplastic syndrome (MDS). We analyzed 256 MDS patients who underwent transplantation from a matched related (n = 133) or matched unrelated (n = 123) donor after 2001. Of the 256, 78 (30.5%) did not receive cytoreductive therapy before HSCT; 40 (15.6%) received chemotherapy, 122 (47.7%) received hypomethylating agents (HMA), and 16 (6.2%) received both (chemo+HMA). Disease status at HSCT defined by International Working Criteria was complete remission in 46 (18%) patients. There were significant differences between therapy groups: there were more therapy-related MDS and higher use of matched related donor in the untreated group. The chemotherapy group had higher serum ferritin levels at HSCT. Patients were older and had more high-risk disease by revised International Prognostic Scoring in the HMA group. Despite those differences, transplantation outcomes were similar in patients who were untreated and who received cytoreductive therapy before HSCT. Three-year event-free survival (EFS) was 44.2%, 30.6%, 34.2%, and 32.8% for untreated, chemotherapy, HMA, and chemo+HMA groups, respectively (P = .50). Multivariate analyses revealed that older age (hazard ratio [HR], 1.3; P = .001); high-risk histologic subtypes, including refractory anemia with excess blasts (HR, 1.5; P = .05) and chronic myelomonocytic leukemia (HR, 2.1; P = .03), high-risk cytogenetics with monosomal karyotype (MK) (HR, 4.0; P < .0001) and high serum ferritin level at HSCT (HR, 1.8; P = .002) were poor prognostic factors for EFS. Bone marrow blast count 5% or higher at HSCT (HR, 1.6; P = .01) and MK (HR, 4.2; P < .0001) were the only prognostic factors for increased relapse incidence after HSCT. Patients with MK represented a poor prognostic group, with 3-year EFS of 11.4% and relapse incidence of 60.9%. In this analysis, various therapy approaches before HSCT did not lead to different transplantation outcomes. Cytogenetics defined by MK was able to identify a very poor prognostic groups that innovative transplantation approaches to improve outcomes are urgently needed.     

The Stem Cell Research Environment: A Patchwork of Patchworks

Few areas of recent research have received as much focus or generated as much excitement and debate as stem cell research. Hope for the therapeutic promise of this field has been matched by social concern associated largely with the sources of stem cells and their uses. This interplay between promise and controversy has contributed to the enormous variation that exists among the environments in which stem cell research is conducted throughout the world. This variation is layered upon intra-jurisdictional policies that are also often complex and in flux, resulting in what we term a ‘patchwork of patchworks’. This patchwork of patchworks and its implications will become increasingly important as we enter this new era of stem cell research. The current progression towards translational and clinical research among international collaborators serves as a catalyst for identifying potential policy conflict and makes it imperative to address jurisdictional variability in stem cell research environments. The existing patchworks seen in contemporary stem cell research environments provide a valuable opportunity to consider how variations in regulations and policies across and within jurisdictions influence research efficiencies and directions. In one sense, the stem cell research context can be viewed as a living experiment occurring across the globe. The lessons to be gleaned from examining this field have great potential for broad-ranging general science policy application.

Impact of Dose-Adjusted Melphalan in Obese Patients Undergoing Autologous Stem Cell Transplantation

Limited guidance exists for dosing melphalan for autologous stem cell transplantation (ASCT) in the obese patient population, because the current literature reports conflicting clinical outcomes between obese and nonobese patients. In 2014, the American Society for Blood and Marrow Transplantation published conditioning chemotherapy dosing guidelines for obese patients and recommended dosing of melphalan using actual body weight (ABW) in the body surface area calculation. The practice at Barnes-Jewish Hospital has consistently been to dose melphalan using adjusted body weight (AdBW), with a 20% correction when a patient weighs ≥120% of his or her ideal body weight (IBW). The purpose of this study was to compare outcomes of melphalan ASCT in patients with multiple myeloma between obese (≥120% IBW) and nonobese (<120% IBW) populations. This retrospective, single-center study included adult patients with multiple myeloma undergoing first ASCT with melphalan conditioning between January 2009 and December 2012. Patient demographic data, transplantation characteristics, and clinical outcomes were collected. The primary outcome was 3-year event-free survival (EFS). Secondary outcomes included response at 100 days post-transplantation, 3-year overall survival, treatment-related mortality (TRM), time to neutrophil engraftment, and hospital length of stay (LOS). To ensure that melphalan dosage adjustment in the obese population did not impact efficacy, the primary outcome was assessed using a noninferiority design, with a predetermined noninferiority margin of 7%. Assuming a 70% 3-year EFS in the nonobese population, a noninferiority margin of 7%, a power of 80%, and an α value of .05, an analysis of 280 patients was required. A total of 270 patients, including 171 (63%) obese patients and 99 (37%) nonobese patients, met our inclusion criteria. Baseline characteristics were well matched between the 2 cohorts, including high-risk cytogenetics, disease severity at diagnosis, and use of maintenance therapy, with the only detectable differences related to weight itself. The 3-year EFS was 41% for the total cohort, with fewer events occurring in the obese cohort compared with the nonobese cohort (51% versus 40%; P?=?.0025). The 95% lower confidence limit established noninferiority. High-risk cytogenetics, disease severity at diagnosis, and therapy response pre- and post-ASCT were all associated with significantly shorter EFS. No between-group differences in TRM, time to engraftment, or hospital LOS were noted. This retrospective, single-center study found that using AdBW to dose melphalan in obese patients was not inferior to the nonobese population in terms of 3-year EFS. This study adds to the limited evidence on melphalan dosing and suggests that transplantation efficacy is not affected by AdBW dosing in obese patients. Further studies are needed to provide additional insight into the pharmacokinetic differences and best dosing practices for obese patients.     

Orchestration of Chemomobilization and G-CSF Administration for Successful Hematopoietic Stem Cell Collection

Successful collection of peripheral blood stem cells (PBSCs) depends on the optimal orchestration of mobilization chemotherapy, granulocyte colony stimulating factor (G-CSF) application, and CD34⁺ cell number assessment in the peripheral blood (PB). However, determining the optimal timing in accordance to the applied chemomobilization regimen can be challenging. Although most centers apply their own local timing schedules, a reliable timetable including the currently most often used mobilization regimens is lacking. We present a comprehensive analysis of the timing modalities for 11 of the most commonly used chemomobilization regimens. A retrospective analysis was performed on the clinical and PBSC collection parameters (including duration of G-CSF application, time point of CD34⁺ assessment, PB CD34⁺ cell count, number of leukapheresis [LP] sessions, processed blood volume, and CD34⁺ collection results) of 91 representatively selected patients who had undergone stem cell mobilization at 2 collection centers.Six to 10 patients were analyzed per regimen with a variety of diagnoses, including multiple myeloma, malignant lymphoma, and sarcoma. No collection failures (<2?×?10⁶ CD34⁺ cells/kg body weight) were observed. All analyzed patients successfully reached their individual collection goal in adherence to the given schedule of chemotherapy, application of G-CSF, measurement of CD34⁺ cells, and subsequent LP.The presented data on the timing of chemomobilization, G-CSF application, and stem cell collection may be helpful in clinical decision making and contribute to a more transparent and predictable treatment process.     

Patient,Virus, and Treatment-Related Risk Factors in Pediatric Adenovirus Infection after Stem Cell Transplantation: Results of a Routine Monitoring Program

Human adenovirus (HAdV) infection after hematopoietic stem cell transplantation (HSCT) is associated with significant morbidity and mortality in children. The optimal surveillance and treatment strategies are under discussion. Here, we present data from 238 consecutive pediatric allogeneic HSCT recipients who underwent transplantation in a single center who were included in a prospective, weekly HAdV DNAemia monitoring program by quantitative PCR. HAdV loads >1000 copies/mL were detected in 15.5% of all patients. Despite a low mortality directly attributed to HAdV infection (2 patients, 0.84%), blood HAdV loads >10,000 copies/mL (6.7% of all patients) were significant and independent risk factors for poor survival. We searched for patient, virus, and treatment-related risk factors of HAdV DNAemia and disease. Detection of HAdV in blood before day 50 post transplantation was a major independent risk factor for the development of blood HAdV loads >10,000 copies/mL. HAdV typing revealed A31, C1, and C2 as the predominant pathogens among several other HAdV strains with type C species detected in most patients with severe HAdV disease. Stool HAdV loads were prospectively monitored in 111 patients and correlated with but did not significantly precede detection in blood. Treatment with cidofovir led to stable or reduced viral load in 70% of patients with blood HAdV loads >1000 copies/mL. Thus, early occurrence of HAdV-DNA in blood of pediatric HSCT recipients predisposes for development of high viral loads. Control of HAdV infections was attempted by preemptive cidofovir treatment of patients with high blood HAdV loads or with symptomatic organ infections and correlated with low HAdV-attributed mortality.