Clinical application of umbilical cord blood (UCB) as a source of hematopoietic stem cells for transplantation is limited by low CD34+ cell dose, increased risk of graft failure, and slow ...hematopoietic recovery. While the cell dose limitation is partially mitigated by using two UCB units, larger-dosed single units would be preferable. We have evaluated the feasibility and safety of StemRegenin-1 (SR-1), an aryl hydrocarbon receptor antagonist that expands CD34+ cells, by placing one of the two units in expansion culture. SR-1 produced a 330-fold increase in CD34+ cells and led to engraftment in 17/17 patients at a median of 15 days for neutrophils and 49 days for platelets, significantly faster than in patients treated with unmanipulated UCB. Taken together, the marked expansion, absence of graft failure, and enhanced hematopoietic recovery support testing of SR-1 expansion as a stand-alone graft and suggest it may ameliorate a limitation of UCB transplant.
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•SR-1 led to significant expansion of CD34+ HSPCs in culture•Seventeen patients with hematological malignancy received SR-1 expanded UCB•SR-1 expanded cells were co-infused with a second unexpanded UCB unit•SR-1 expansion improved neutrophil and platelet recovery compared to controls
Clinical testing of the aryl hydrocarbon antagonist StemRegenin-1 showed robust expansion of hematopoietic stem and progenitor cells and an adequate safety profile in the setting of double UCB transplant, supporting its further testing for safety and efficacy as a stand-alone graft after myeloablative conditioning.
The use of two units of cord blood to reconstitute hematopoiesis in transplantation for relapsed hematologic cancers in patients 1 to 21 years of age proved to be no better and was in some ways worse ...than the standard one-unit transplant.
Since 1993, unrelated-donor umbilical-cord blood has been used as the source of hematopoietic stem cells for transplantation in an estimated 30,000 patients with malignant and nonmalignant diseases.
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As compared with stem-cell grafts from adult donors, cord blood has the advantages of more rapid availability, relative absence of donor attrition, and, after transplantation, a reduced risk of graft-versus-host disease (GVHD) despite donor–recipient HLA disparity.
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In addition, less restriction on HLA matching permits greater use of cord blood for members of racial minorities, who are less likely to have a suitably HLA-matched volunteer adult donor.
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However, the use of cord blood . . .
The development of innovative wearable technologies has raised great interest in new means of data collection in healthcare and biopharmaceutical research and development. Multiple applications for ...wearables have been identified in a number of therapeutic areas; however, researchers face many challenges in the clinic, including scientific methodology as well as regulatory, legal, and operational hurdles. To facilitate further evaluation and adoption of these technologies, we highlight methodological and logistical considerations for implementation in clinical trials, including key elements of analytical and clinical validation in the specific context of use (COU). Additionally, we provide an assessment of the maturity of the field and successful examples of recent clinical experiments.
The purpose of this paper is to integrate the concepts of ecosystem services and disservices when assessing the efficacy of using urban forests for mitigating pollution. A brief review of the ...literature identifies some pollution mitigation ecosystem services provided by urban forests. Existing ecosystem services definitions and typologies from the economics and ecological literature are adapted and applied to urban forest management and the concepts of ecosystem disservices from natural and semi-natural systems are discussed. Examples of the urban forest ecosystem services of air quality and carbon dioxide sequestration are used to illustrate issues associated with assessing their efficacy in mitigating urban pollution. Development of urban forest management alternatives that mitigate pollution should consider scale, contexts, heterogeneity, management intensities and other social and economic co-benefits, tradeoffs, and costs affecting stakeholders and urban sustainability goals.
Environmental managers should analyze ecosystem services and disservices when developing urban forest management alternatives for mitigating urban pollution.
The replication crisis in the social and psychological sciences is said to be due in part to publication bias and the resulting file drawer problem. Meta-analysis is often advocated as a means of ...resolving this crisis but is prone to the same publication bias and file drawer effects. A study of 23 meta-analyses examined the consequences of correcting for these effects through the inclusion of unpublished research. Results indicated that the inclusion of unpublished data led to smaller meta-analytic means in some instances, consistent with the primary theorized effects of the file drawer problem and publication bias, but led to larger meta-analytic means in nearly as many instances, suggesting the presence and influence of other, unknown artifacts in unpublished research. These findings suggest that meta-analysis is limited in its ability to resolve the replication crisis and instead may introduce unexplained effects that render cumulative science problematic.
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BFBNIB, DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, UILJ, UKNU, UL, UM, UPUK
A meta-analysis reported in this article compared the effects of ontological and utilitarian measures of individualism and collectivism on the findings of published research. Ontological differences ...in individualism and collectivism concern the degree to which either individuals or collectivities are interpreted as the primary entities comprising social reality. Reflecting these differences are measures that include subjects such as the degree of permanence and sense of collective obligation associated with interpersonal, group, or community relationships. Utilitarian distinctions in individualism and collectivism involve beliefs that either individuals or collectivities are instrumental in the pursuit of valued outcomes. Related measures include items concerning the attractiveness or consequences of working alone versus working in a group. Results of the meta-analysis indicated that ontological and utilitarian measures have produced differing findings in several notable instances, with utilitarian measures producing larger effects.
The first hematopoietic transplant in which umbilical cord blood (UCB) was used as the source of hematopoietic cells was performed in October 1988. Since then, significant achievements have been ...reported in terms of our understanding of the biology of UCB-derived hematopoietic stem (HSCs) and progenitor (HPCs) cells. Over 40,000 UCB transplants (UCBTs) have been performed, in both children and adults, for the treatment of many different diseases, including hematologic, metabolic, immunologic, neoplastic, and neurologic disorders. In addition, cord blood banking has been developed to the point that around 800,000 units are being stored in public banks and more than 4 million units in private banks worldwide. During these 30 years, research in the UCB field has transformed the hematopoietic transplantation arena. Today, scientific and clinical teams are still working on different ways to improve and expand the use of UCB cells. A major effort has been focused on enhancing engraftment to potentially reduce risk of infection and cost. To that end, we have to understand in detail the molecular mechanisms controlling stem cell self-renewal that may lead to the development of ex vivo systems for HSCs expansion, characterize the mechanisms regulating the homing of HSCs and HPCs, and determine the relative place of UCBTs, as compared to other sources. These challenges will be met by encouraging innovative research on the basic biology of HSCs and HPCs, developing novel clinical trials, and improving UCB banking both in the public and private arenas.
Repair of DNA interstrand crosslinks requires action of multiple DNA repair pathways, including homologous recombination. Here, we report a de novo heterozygous T131P mutation in RAD51/FANCR, the key ...recombinase essential for homologous recombination, in a patient with Fanconi anemia-like phenotype. In vitro, RAD51-T131P displays DNA-independent ATPase activity, no DNA pairing capacity, and a co-dominant-negative effect on RAD51 recombinase function. However, the patient cells are homologous recombination proficient due to the low ratio of mutant to wild-type RAD51 in cells. Instead, patient cells are sensitive to crosslinking agents and display hyperphosphorylation of Replication Protein A due to increased activity of DNA2 and WRN at the DNA interstrand crosslinks. Thus, proper RAD51 function is important during DNA interstrand crosslink repair outside of homologous recombination. Our study provides a molecular basis for how RAD51 and its associated factors may operate in a homologous recombination-independent manner to maintain genomic integrity.
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•A dominant-negative mutation in RAD51 is identified in Fanconi anemia-like patient•RAD51 T131P-expressing cells are ICL repair defective but HR proficient•RAD51 T131P has unregulated ATPase activity poisoning wild-type RAD51•Defective RAD51 function results in DNA2/WRN-dependent degradation of DNA
Defects in DNA interstrand crosslink (ICL) repair have detrimental consequences, including stem cell failure and tumorigenesis. Wang et al. uncover a new subtype of Fanconi anemia, FA-R, in which a de novo negative co-dominant RAD51 (FANCR) mutation results in ICL repair defect without affecting RAD51-dependent homologous recombination.
Disruption of gene silencing by Polycomb protein complexes leads to homeotic transformations and altered developmental-phase identity in plants. Here we define short genomic fragments, known as ...Polycomb response elements (PREs), that direct Polycomb repressive complex 2 (PRC2) placement at developmental genes regulated by silencing in Arabidopsis thaliana. We identify transcription factor families that bind to these PREs, colocalize with PRC2 on chromatin, physically interact with and recruit PRC2, and are required for PRC2-mediated gene silencing in vivo. Two of the cis sequence motifs enriched in the PREs are cognate binding sites for the identified transcription factors and are necessary and sufficient for PRE activity. Thus PRC2 recruitment in Arabidopsis relies in large part on binding of trans-acting factors to cis-localized DNA sequence motifs.
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