Successful unrelated marrow transplantation for patients over the age of 40 with chronic myelogenous leukemia

AbstractSome older patients (> or =40 years) with chronic myelogenous leukemia (CML) who lack human leukocyte antigen (HLA)-identical sibling donors are not offered unrelated marrow transplantation because of concerns over excessive regimen-related toxicity, in particular due to graft-vs.-host disease (GVHD). The purpose of this study was to determine the efficacy and toxicity of unrelated marrow transplantation in older CML patients using a regimen designed to minimize the severity of GVHD. Thirty-one consecutive patients over the age of 40 with CML received unrelated marrow transplants between January 1988 and June 1997. Twenty-one patients were transplanted in chronic phase while ten were transplanted in the accelerated phase of their disease. Fifteen patients received transplants from phenotypically matched donors while 16 received marrow grafts from donors who were mismatched at one HLA locus. GVHD prophylaxis consisted of ex vivo T cell depletion of the donor marrow graft plus posttransplant cyclosporine administration. Durable engraftment was achieved in 29 of 31 patients (94%). The probability of developing grades II-IV or severe grades III-IV acute GVHD was 39.2 and 7.1%, respectively. There was no difference in the incidence of grades II-IV acute GVHD between patients transplanted with marrow grafts from phenotypically matched (38.1%) vs. those transplanted from mismatched unrelated donors (40%, p = 0.99). The 2-year probability of relapse for the entire population was 29.4%. Relapse was significantly higher for patients transplanted in accelerated phase (60%) than for those in chronic phase (13.8%, p = 0.027). The 2-year probability of overall survival and disease-free survival for the entire cohort was 56 and 45%, respectively. There was no significant difference in survival or disease-free survival for patients receiving phenotypically matched vs. mismatched marrow grafts. Immunological reconstitution for this cohort was compared with a younger (<40 years) patient population that had been similarly transplanted over the same time period. Immune function as assessed by total T cell, B cell, NK cell, and T cell subset reconstitution posttransplant was quantitatively equivalent in the two groups with most parameters normalizing within 18 months of transplant. We conclude that CML patients over the age of 40 who have either phenotypically matched or one antigen-mismatched unrelated donors can successfully undergo allogeneic marrow transplantation. T cell depletion of the marrow graft may be advantageous in these older patients by reducing GVHD severity, particularly in those patients transplanted with HLA-disparate marrow grafts.Biol Blood Marrow Transplant 1998;4(1):3-12

Chaperone-dependent Regulation of Endothelial Nitric-oxide Synthase Intracellular Trafficking by the Co-chaperone/Ubiquitin Ligase CHIP

Endothelial nitric-oxide synthase (eNOS), the enzyme responsible for production of endothelial NO, is under tight and complex regulation. Proper cellular localization of eNOS is critical for optimal coupling of extracellular stimulation with NO production. In addition, the molecular chaperone Hsp90 interacts with eNOS and positively regulates eNOS activity. Hsp90 is modulated by physical interaction with its co-chaperones. CHIP (carboxyl terminus of Hsp70-interacting protein) is such a co-chaperone that remodels the Hsp90 heterocomplex and causes protein degradation of some Hsp90 substrates through the ubiquitin-protein isopeptide ligase activity of CHIP. Here we show that CHIP incorporated into the eNOS.Hsp90 complex and specifically decreased soluble eNOS levels in transiently transfected COS cells. Surprisingly, in contrast to the effects of the Hsp90 inhibitor geldanamycin, which induces eNOS ubiquitylation and its subsequent protein degradation, CHIP did not target eNOS for ubiquitylation and proteasome-dependent degradation. Instead, CHIP partitioned soluble eNOS into an insoluble and inactive cellular compartment, presumably through its co-chaperone activity. This effect seems to be due to displacement of eNOS from the Golgi apparatus, which is otherwise required for trafficking of eNOS to the plasmalemma and subsequent activation. Consistent with observations from overexpression studies, eNOS localization to the membrane and activity were increased in mouse lung endothelial cells lacking CHIP. Taken together, these results demonstrate a novel co-chaperone-dependent mechanism through which eNOS trafficking is regulated and suggest a potentially generalized role for CHIP in protein trafficking through the Golgi compartment

AI for a Generative Economy: The Role of Intelligent Systems in Sustaining Unalienated Labor, Environment, and Society

Extractive economies pull value from a system without restoring it. Unsustainable extraction of ecological value includes over-fishing, clear-cut logging, etc. Extraction of labor value is similarly objectionable: assembly line jobs for example increase the likelihood of cardiovascular disease, depression, suicide and other problems. Extraction of social value--vacuuming up online personal information, commodification of the public sphere, and so on-- constitutes a third form. But all three domains--ecological value, labor value, and social value--can thrive in unalienated forms if we can create a future of work that replaces extraction with generative cycles. AI is a key technology in developing these alternative economic forms. This paper describes some initial experiments with African, African American, and Native American artisans who were willing to experiment with the introduction of computational enhancements to their work. Following our report on these initial results, we map out a vision for how AI could scale up labor that sustains “heritage algorithms”, ecologically situated value chains and other hybrid forms that prevent value alienation while flourishing from its robust circulation.NSF grant DRL-1640014NSF grant DGE-0947980Peer Reviewedhttps://deepblue.lib.umich.edu/bitstream/2027.42/150647/1/FSS-19_paper_64.pdfDescription of FSS-19_paper_64.pdf : Preprint Versio

Automation for the Artisanal Economy: Enhancing the Economic and Environmental Sustainability of Crafting Professions with Human-Machine Collaboration

Artificial intelligence (AI) is poised to eliminate millions of jobs, from finance to truck driving. But artisanal products—(e.g. handmade textiles) are valued precisely because of their human origins, and thus have some inherent “immunity” from AI job loss. At the same time, artisanal labor, combined with technology, could potentially help to democratize the economy, allowing independent, small scale businesses to flourish. Could AI, robotics and related automation technologies enhance the economic viability and environmental sustainability of these beloved crafting professions, perhaps even expanding their niche to replace some job loss in other sectors? In this paper we compare the problems created by the current mass production economy, and potential solutions from an artisanal economy. In doing so, the paper details the possibilities of utilizing AI to support hybrid forms of human-machine production at the micro-scale; localized and sustainable value chains at the meso-scale; and networks of these localized and sustainable producers at the macro scale. In short, a wide range of automation technologies are potentially available for facilitating and empowering an artisanal economy. Ultimately, it is our hope that this paper will facilitate a discussion on a future vision for more “generative” economic forms in which labor value, ecological value and social value can circulate without extraction or alienation.National Science Foundation DRL-1640014National Science Foundation DGE-0947980Peer Reviewedhttps://deepblue.lib.umich.edu/bitstream/2027.42/150492/1/Eglash et al. accepted in 2019.pdfDescription of Eglash et al. accepted in 2019.pdf : Preprint Versio

A Conditional Yeast E1 Mutant Blocks the Ubiquitin–Proteasome Pathway and Reveals a Role for Ubiquitin Conjugates in Targeting Rad23 to the Proteasome

E1 ubiquitin activating enzyme catalyzes the initial step in all ubiquitin-dependent processes. We report the isolation of uba1-204, a temperature-sensitive allele of the essential Saccharomyces cerevisiae E1 gene, UBA1. Uba1-204 cells exhibit dramatic inhibition of the ubiquitin–proteasome system, resulting in rapid depletion of cellular ubiquitin conjugates and stabilization of multiple substrates. We have employed the tight phenotype of this mutant to investigate the role ubiquitin conjugates play in the dynamic interaction of the UbL/UBA adaptor proteins Rad23 and Dsk2 with the proteasome. Although proteasomes purified from mutant cells are intact and proteolytically active, they are depleted of ubiquitin conjugates, Rad23, and Dsk2. Binding of Rad23 to these proteasomes in vitro is enhanced by addition of either free or substrate-linked ubiquitin chains. Moreover, association of Rad23 with proteasomes in mutant and wild-type cells is improved upon stabilizing ubiquitin conjugates with proteasome inhibitor. We propose that recognition of polyubiquitin chains by Rad23 promotes its shuttling to the proteasome in vivo

The International Gene Trap Consortium Website: a portal to all publicly available gene trap cell lines in mouse

Gene trapping is a method of generating murine embryonic stem (ES) cell lines containing insertional mutations in known and novel genes. A number of international groups have used this approach to create sizeable public cell line repositories available to the scientific community for the generation of mutant mouse strains. The major gene trapping groups worldwide have recently joined together to centralize access to all publicly available gene trap lines by developing a user-oriented Website for the International Gene Trap Consortium (IGTC). This collaboration provides an impressive public informatics resource comprising ∼45 000 well-characterized ES cell lines which currently represent ∼40% of known mouse genes, all freely available for the creation of knockout mice on a non-collaborative basis. To standardize annotation and provide high confidence data for gene trap lines, a rigorous identification and annotation pipeline has been developed combining genomic localization and transcript alignment of gene trap sequence tags to identify trapped loci. This information is stored in a new bioinformatics database accessible through the IGTC Website interface. The IGTC Website () allows users to browse and search the database for trapped genes, BLAST sequences against gene trap sequence tags, and view trapped genes within biological pathways. In addition, IGTC data have been integrated into major genome browsers and bioinformatics sites to provide users with outside portals for viewing this data. The development of the IGTC Website marks a major advance by providing the research community with the data and tools necessary to effectively use public gene trap resources for the large-scale characterization of mammalian gene function

Modeling Insertional Mutagenesis Using Gene Length and Expression in Murine Embryonic Stem Cells

Background. High-throughput mutagenesis of the mammalian genome is a powerful means to facilitate analysis of gene function. Gene trapping in embryonic stem cells (ESCs) is the most widely used form of insertional mutagenesis in mammals. However, the rules governing its efficiency are not fully understood, and the effects of vector design on the likelihood of genetrapping events have not been tested on a genome-wide scale. Methodology/Principal Findings. In this study, we used public gene-trap data to model gene-trap likelihood. Using the association of gene length and gene expression with gene-trap likelihood, we constructed spline-based regression models that characterize which genes are susceptible and which genes are resistant to gene-trapping techniques. We report results for three classes of gene-trap vectors, showing that both length and expression are significant determinants of trap likelihood for all vectors. Using our models, we also quantitatively identifie

Ethnocomputing: the Design and Assessment of Culture-Based Learning Software for Math and Computing Education

The United States has a serious problem in Science, Technology, Engineering, and Mathematics. The STEM disciplines are suffering from a `Quiet Crisis'[1]. The problem is that African Americans, Latino/a, Native American, and other ethnic minority students are choosing careers in the STEM disciplines at lower percentages than their white and Asian counterparts [2]. We refer to this disparity as underrepresentation. This work focuses on the use of the Culturally Situated Design Tools (CSDTs, http://csdt.rpi.edu) as a means to counter this underrepresentation. The programmable set of CSDTs represents the development of this software from being focused on ethnomathematics, to ethnocomputing. Ethnocomputing is the reproduction of cultural artifacts in simulation. The CSDTs are part of the constructionist genre of programmable software that seeks to teach computer science concepts to students as they construct these cultural artifacts. Development work on the programmable CSDT software has provided the opportunity to examine the challenges that occur in cross cultural software development using the Agile method. This work includes ethnographic user and developer stories that have informed the development of the pCSDT software. Among the challenges of developing this software has been negotiating the controversy of what we have come to term "The Content Agnostic Position". This is the notion that all software with objects in simulation, regardless of what those objects are, possesses equal value in teaching students. This position, however, often results in the commercial or violent colonization of user spaces by corporate produced media objects and simulated gun violence. It is our view that this colonization can be diminished through the use of cultural objects in simulation, such as those found in the CSDTs. Our work is intended to create a decolonized space for mathematics and computing education. This work also reports the findings of a quasi-experiment conducted with junior high school students in Kumasi, Ghana, West Africa during the summer of 2014

Software Design in the 'Construction Genre' of Learning Technology: Content Aware versus Content Agnostic

This article describes and critiques a phenomenon that we identify as content agnosticism in the ?construction genre? of educational software. Our thesis is that the content agnostic position ? the assumption that any technology which supports constructionist learning theories must act as a blank slate or empty container ? has been erroneously presented as the single trajectory towards the development and implementation of constructionist technologies. We survey some of the disadvantages to the content agnostic position, ranging from violent video game formats to ways in which consumption practices perform a corporate colonization of childhood. As an alternative framework we reconsider the constructionism ? instructionism continuum as just one of two orthogonal dimensions; here both content agnostic and content aware constructionist positions are possible. We review some successful content aware design in math and computing education, and finally provide a detailed case study of Culturally Situated Design Tools (CSDTs), as an example of how constructionism can be combined with a content aware approach to math and computing software design