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Branford, CT, United States

Lu C.,University of Minnesota | Huang X.,University of Minnesota | Zhang X.,University of Minnesota | Roensch K.,University of Minnesota | And 5 more authors.
Blood | Year: 2011

Dendritic cells (DCs) are potent antigen-presenting cells derived from hematopoietic progenitor cells and circulating monocytes. To investigate the role of microRNAs (miRNAs) during DC differentiation, maturation, and function, we profiled miRNA expression in human monocytes, immature DCs (imDCs), and mature DCs (mDCs). Stage-specific, differential expression of 27 miRNAs was found during monocyte differentiation into imDCs and mDCs. Among them, decreased miR-221 and increased miR-155 expression correlated with p27 kip1 accumulation in DCs. Silencing of miR-221 or overexpressing of miR-155 in DCs resulted in p27 kip1 protein increase and DC apoptosis. Moreover, mDCs from miR-155 -/- mice were less apoptotic than those from wild-type mice. Silencing of miR-155 expression had little effect on DC maturation but reduced IL-12p70 production, whereas miR-155 overexpression in mDCs enhanced IL-12p70 production. Kip1 ubiquitination-promoting complex 1, suppressor of cytokine signaling 1, and CD115 (M-CSFR) were functional targets of miR-155. Furthermore, we provide evidence that miR-155 indirectly regulated p27 kip1 protein level by targeting Kip1 ubiquitination-promoting complex 1. Thus, our study uncovered miRNA signatures during monocyte differentiation into DCs and the new regulatory role of miR-221 and miR-155 in DC apoptosis and IL-12p70 production. © 2011 by The American Society of Hematology.

MacMillan M.L.,University of Minnesota | DeFor T.E.,University of Minnesota | DeFor T.E.,Core Informatics | Weisdorf D.J.,University of Minnesota
Blood | Year: 2010

The optimal primary endpoint for acute graft-versus-host disease (GVHD) therapeutic trials has not been established. In a retrospective analysis, we examined the response of 864 patients who received prednisone 60 mg/m 2/d for 14 days, followed by an 8-week taper, as initial therapy for acute GVHD from 1990-2007 at the University of Minnesota. Patients received grafts of human leukocyte antigen-matched sibling bone marrow (BM) or peripheral blood (PB; n = 315), partially matched sibling BM or PB (n = 24), unrelated donor BM or PB (n = 313), single (n = 89) or double (n = 123) umbilical cord blood. Day 28 responses were similar to day 56 responses and better than day 14 responses in predicting transplantation-related mortality (TRM). In multiple regression analysis, patients with no response at day 28 were 2.78 times (95% CI, 2.17-3.56 times; P < .001) more likely to experience TRM before 2 years than patients with a response. Other factors associated with significantly worse 2-year TRM include older age, high-risk disease, severe GVHD, and partially matched related BM/PB. No other differences in response by donor source were observed. These data suggest that day 28 is the best early endpoint for acute GVHD therapeutic trials in predicting 2-year TRM. © 2010 by The American Society of Hematology.

Limou S.,Center for Cancer Research | Dummer P.D.,U.S. National Institutes of Health | Nelson G.W.,Core Informatics | Kopp J.B.,U.S. National Institutes of Health | Winkler C.A.,Center for Cancer Research
Kidney International | Year: 2015

The discovery that two common APOL1 alleles were strongly associated with nondiabetic kidney diseases in African descent populations led to hope for improved diagnosis and treatment. Unfortunately, we still do not have a clear understanding of the biological function played by APOL1 in podocytes or other kidney cells, nor how the renal risk alleles initiate the development of nephropathies. Important clues for APOL1 function may be gleaned from the natural defense mechanism of APOL1 against trypanosome infections and from similar proteins (e.g., diphtheria toxin, mammalian Bcl-2 family members). This review provides an update on the biological functions for circulating (trypanosome resistance) and intracellular (emerging role for autophagy) APOL1. Further, we introduce a multimer model for APOL1 in kidney cells that reconciles the gain-of-function variants with the recessive inheritance pattern of APOL1 renal risk alleles. © 2015 International Society of Nephrology.

Holtan S.G.,University of Minnesota | DeFor T.E.,Core Informatics | Lazaryan A.,University of Minnesota | Bejanyan N.,University of Minnesota | And 5 more authors.
Blood | Year: 2015

The success of allogeneic hematopoietic cell transplantation (HCT) is typically assessed as individual complications, including graft-versus-host disease (GVHD), relapse, or death, yet no one factor can completely characterize cure without ongoing morbidity. We examined a novel composite end point of GVHD-free/relapse-free survival (GRFS) in which events include grade 3-4 acute GVHD, systemic therapy-requiring chronicGVHD, relapse, or death in the first post-HCT year. In 907 consecutive University of Minnesota allogeneic HCT recipients (2000-2012), 1-year GRFS was 31% (95% confidence interval [CI] 28-34). Regression analyses showed age, disease risk, and donor type significantly influencing GRFS. Adults age 21+ had 2-fold worseGRFSvs children;GRFSdid not differ beyondage 21. Adjusted for conditioning intensity, stem cell source, disease risk, age, and transplant year, HLA-matched sibling donor marrow resulted in the best GRFS (51%, 95% CI 46-66), whereas HLA-matched sibling donor peripheral blood stem cells were significantly worse (25%, 95% CI 20-30, P = .01). GRFS after umbilical cord blood transplants and marrowfrommatched unrelated donors were similar (31%, 95% CI 27-35 and 32%, 95% CI 22-42, respectively). BecauseGRFSmeasures freedom fromongoingmorbidity and represents ideal HCT recovery, GRFS has value as a novel end point for benchmarking new therapies. (Blood. 2015;125(8):1333-1338) © 2015 by The American Society of Hematology.

MacMillan M.L.,University of Minnesota | Defor T.E.,University of Minnesota | Defor T.E.,Core Informatics | Weisdorf D.J.,University of Minnesota
British Journal of Haematology | Year: 2012

To define high-risk acute graft-versus-host disease (GVHD) at onset, we examined the initial GVHD stage and grade of 864 patients at the University of Minnesota who received uniform therapy with prednisone 60 mg/m 2 per d. We compared the prognostic utility of the Minnesota (MN; modified from Consensus) versus Center for International Blood and Marrow Transplant Research (CIBMTR) GVHD organ stage-derived grading systems. As neither GVHD grading system optimally predicted outcomes, a novel acute GVHD risk score was devised by combining the MN and CIBMTR systems. Using multiple regression analysis, we could dichotomize patients into high risk (HR, n = 86) acute GVHD with initial grade IIIC, IIID or IVD who were less likely to respond to steroid therapy by day 28 [relative risk (RR), 0·3, P < 0·001] and had a higher risk for transplant-related mortality (RR, 2·0, P < 0·001) than patients with standard risk (SR, initial grade IA-IIIB, n = 778) GVHD. Using this novel acute GVHD Risk Score, HR GVHD is either skin stage 4, lower gastrointestinal (GI) stage 3+, liver stage 3+, or skin stage 3 and lower GI or liver stage 2+ GVHD. Patients with HR acute GVHD have a poor prognosis, require alternative initial therapy and should be the focus of novel therapeutic trials. © 2012 Blackwell Publishing Ltd.

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