Browsing by Subject "Transplant"

Now showing 1 - 6 of 6
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    Adaptation and innovation of anti-cancer epigenetic targeting therapeutic strategies for the treatment of murine chronic graft vs host disease
    (2021-08) Zaiken, Michael
    Each year in the United States nearly 200,000 patients receive a diagnosis of a hematological cancer. While the treatment of these conditions has improved remarkably over the last few decades, nearly a quarter of these patients are expected to die from their disease. Much of the improvement in treatment comes from advancements in the field of allogenic hematopoietic stem cell transplant (aHSCT), the only curative therapy for the treatment of hematological malignancies. While aHSCT is an incredibly powerful technique, it comes with the major drawback of inducing graft vs host disease (GVHD), the second leading cause of mortality following aHSCT after reoccurrence of the original disease. Chronic GVHD in particular has proven difficult to manage. cGVHD is an auto-immune-like condition that arises as a result of donor-derived immune cells attacking the recipient tissues post-transplant. The current standard of treatment for cGVHD involves broad steroid immunosuppression, however in cases where steroid refractory forms of the disease arise treatment options are extremely limited. Murine modeling of cGVHD has proven to be a highly effective method for the development and preclinical testing of novel therapies. Based on these studies, it has been determined that the germinal center reaction (GCR) forms a critical step in the pathogenesis of cGVHD, as it is necessary for the development of allo-antibodies that drive fibrotic tissue damage which characterizes the condition. As such, the development of novel therapeutics that disrupt this reaction is of particular interest for the treatment of cGVHD. Epigenetic targeting drugs inhibit enzymes involved in chromatin remodeling and changing the epigenetic landscape of cells. Their use in cancer treatment is primarily driven by the drug’s impact on the aberrant epigenome that arises in cancer cells. In the studies presented here, we sought to leverage this strategy for the treatment of cGVHD, not by targeting aberrant epigenomic changes, but instead using these compounds to disrupt cellular processes necessary for the pathogenesis of cGVHD in particular the GCR. To that end, we tested the preclinical efficacy of three different classes of epigenetic targets in the treatment of cGVHD. We first investigated the potential of BET-bromodomain inhibitor JQ1, which inhibits a number of epigenetic reader enzymes, in particular BRD4. We show that while JQ1 has great impact in a fibrotic model of cGVHD that recapitulates pulmonary dysfunction from bronchiolitis obliterans (BOS), its impact in inflammatory models of GVHD is limited. Next, we tested the role of the epigenetic writer EZH2 in the pathogenesis and treatment of cGVHD. We show that not only is EZH2 necessary for the establishment of cGVHD, but that a novel small molecule inhibitor of EZH2, JQ5, is highly effective in treating multiple murine models of the disease. We further demonstrate that while both of these strategies disrupt the GCR, they do so through the regulation of unique sets of genetic targets, which may have important implications for their clinical translation. Finally, we tested the role of the dynamic DNA demethylases TET2 and TET3 in cGVHD. We show that TET3 is critical for the initiation of disease not through inhibition of the GCR, but by changing the reaction to alter the IgG class switching of antibody secreting B cells. In doing so Tet3 loss of function prevents the development of fibrotic pathology while preserving adaptive immune activity. These trials demonstrate not only the preclinical efficacy of these therapeutic targets but show that the targeting of epigenetic regulators of the GCR is a viable avenue for the development of further therapies for the treatment of cGVHD.
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    Aquatic macrophyte response to carp removal and the success of transplanting aquatic macrophytes to restore the littoral community
    (2014-05) Knopik, Joshua Michael
    Aquatic macrophytes play a significant role in maintaining water quality and ecosystem health. They provide refuge for algae-consuming zooplankton, stabilize sediment, consume nutrients, and provide habitat for aquatic vertebrates. However, high densities of non-native invasive macrophytes can cause harm to the lake ecosystem. A healthy aquatic macrophyte community consists of a diversity of native taxa. Common carp, an invasive species, can disrupt native macrophyte communities. High densities of common carp uproot aquatic macrophytes and stir up sediments, encouraging a turbid water state and low density of macrophytes. Water clarity and aquatic macrophytes will likely increase after the removal of common carp. However, it can take several years for native macrophytes to return after a large-scale fish manipulation. There is also concern that non-native invasive macrophytes will quickly dominate the littoral zone after carp removal.I evaluated the response of the aquatic macrophyte community, between 2009 and 2012, after the large scale removal of common carp from Lake Susan, Carver County, MN (MN DNR DOW ID 10-001300). To assess plant frequency of occurrence, plant communities were assessed using a point intercept survey method in the spring and mid-summer. To quantify changes in plant biomass, approximately 40 random biomass samples were taken during each survey. To further understand response of Eurasian watermilfoil (Myriophyllum spicatum), a non-native invasive plant, milfoil herbivore surveys were also conducted throughout each summer. To evaluate recruitment potential of the non-native curlyleaf pondweed (Potamogeton crispus) turions were sampled each October. Comparisons of the plant community were done between the years to understand the succession of natural plant recruitment.To promote the recruitment of native plants, I transplanted six native taxa from nearby Lake Ann into Lake Susan to increase the species richness and distribution macrophytes within the lake. Four separate transplant experiments were conducted, each assessing a different variable. The primary focus of experiment one was to assess the survival of selected taxa and compare growth between open locations and those protected from herbivore access. The primary focus of experiment two was to increase the number of transplant locations geographically around the littoral zone, and correlate environmental growth factors (light, sediment bound nitrogen, sediment bulk density, sediment organic matter, and wave protection behind lily beds), to the expansion of the transplanted taxa. Experiment three tested transplant survival and expansion at greater depths. Experiment four evaluated if earlier planting of transplants improved survival of deeper transplants.There was an increase in the diversity and overall abundance of submersed aquatic macrophytes in Lake Susan after common carp population was reduced. Species richness increased naturally from 13 taxa in 2009 to 14 in 2012. The number of sites with moderate diversity (>4 taxa per site) increased from 8 sites to 2009 to 12 sites in 2012. There was also an increase in the frequency of occurrence of most taxa. Total dry shoot biomass of both native and invasive taxa also showed a statistically significant increase (p <0.001). The non-native curlyleaf pondweed increased significantly from 17% of sites in 2009 to 41% of sites by 2011. Eurasian watermilfoil decreased in frequency and biomass between 2009 and 2012. This decline, with the persistent high density of milfoil weevils suggests the weevils provided effective biocontrol of Eurasian watermilfoil. Transplanting whole adult plants in shallow water (<1 meter) was generally successful for the duration of this study (four years). Most transplanted taxa showed survival during the initial growing season. Overwintering success was a better predictor of long term success than initial survival and protection from by lily beds. Wild celery (Vallisnaria americana), and water-stargrass (Zosterella dubia) had the highest survival, whereas bushy pondweed (Najas flexilis), and muskgrass (Chara spp.), had inconsistent survival, and northern watermilfoil (Myriophyllum sibiricum), largely failed to survive. The most important environmental factor in the success and expansion of transplants was depth, which affected light availability. Whole plants transplanted into deeper zones (approximately 1.4m depth) failed due to low light (summer Secchi depths were often <1.0m). Both native and non-native aquatic macrophytes responded favorably to the removal of high carp densities, and transplanting aquatic macrophytes can help to restore the littoral community.
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    Cryopreservation of Pancreatic Islets Experimental Data Repository 2022
    (2022-01-18) Bischof, John, C; Finger, Erik, B; efinger@umn.edu; Finger, Erik, B; University of Minnesota Organ and Tissue Preservation Group
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    Differentially Expressed Gene Transcripts Using RNA Sequencing from the Blood of Immunosuppressed Kidney Allograft Recipients
    (2016-02-29) Dorr, Casey; Wu, Baolin; Guan, Weihua; Muthusamy, Amutha; Sanghavi, Kinjal; Schladt, David; Maltzman, Jonathan; Scherer, Steven; Brott, Marcia; Matas, Arthur; Jacobson, Pamala; Oetting, William; Israni, Ajay; isran001@umn.edu; Israni, Ajay
    This is the FPKM and clinical covariate data from a paper in PLOS One. These data will be useful for future researchers to study gene expression patterns over time before and after immunosuppression and kidney transplantation. We removed subject names and any other identifiers in order to de-identify the subjects.
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    Moderators of the effectiveness of a mindfulness-based stress reduction intervention compared to an active control for solid organ transplant patients.
    (2010-08) Sherr, Laura Jayne
    Psychological distress and sleep disturbance are common among post-operative transplant patients. Mindfulness-Based Stress Reduction (MBSR) may be helpful in providing relief for these symptoms without interfering with a demanding medication regimen. This study is based on the Wellness Intervention After Transplant Study (Gross, Kreitzer, Thomas, Reilly-Spong, Cramer-Bornemann, Nyman, Frazier, & Ibrahim, in press) and evaluated moderators of the effectiveness of MBSR compared to an active control group for reducing depression, anxiety, and sleep dysfunction. The active control group was referred to as Health Education (HE) and was based on Stanford University's Chronic Disease Self-Management Program (Lorig et. al, 2000). It was hypothesized that individuals with greater levels of depression, anxiety, and sleep disturbance, and fewer psychosocial resources (mindfulness and self-efficacy) would benefit from either intervention more than individuals with less distress and more psychosocial resources. Additionally, individuals would do better in the intervention that targeted the domain in which they were lacking (e.g. those with lower baseline mindfulness would do better in MBSR than HE; those with lower baseline self-efficacy would do better in HE than MBSR). Participants consisted of 127 solid organ transplant recipients who were at least six months post-surgery, randomized to either the MBSR or HE groups, and completed baseline and post-intervention (8-week) assessments. Results indicated that participants with fewer psychosocial resources and greater distress did better in the HE group in regards to reducing symptoms. This pattern did not hold for those in the MBSR group where individuals with greater psychosocial resources reduced symptoms; whereas those with more distress and fewer resources increased in symptoms.
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    Precision Medicine Approaches to Immunosuppression Using Pharmacogenomics and the Microbiome
    (2022-08) Saqr, Abdelrahman
    In this thesis, I provide two examples of precision medicine applications to currently unsolved drug related problems. In chapter 1, the influence of the microbiome on the enterohepatic recirculation of mycophenolate mofetil (MMF) in hematopoietic stem cell transplant recipients (HCT) is described. There is substantial unexplained interindividual variability in MMF pharmacokinetics. This work illustrates that variability in the gut microbiome composition is associated with enterohepatic recirculation of the mycophenolic acid (MPA), the active metabolite of MMF, and consequently differences in drug exposure. In chapter 2, the influence of CYP3A4 and CYP3A5 genotypes on the magnitude of the drug-drug interaction between tacrolimus and steroids in kidney transplant recipients is described. This drug-drug interaction, while well-known, is unpredictable. Some individuals have an induction of tacrolimus clearance in the presence of steroids and others have little to no changes in clearance. This analysis shows that individuals who carry a loss of function allele such as CYP3A5*3 have a minor and clinically insignificant drug-drug interaction whereas individuals who express CYP3A5 and carry at least one CYP3A5*1 allele have a significant tacrolimus-steroid interaction which results in higher tacrolimus dose requirements during steroid use.