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Partial-volume correction increases estimated dopamine D2-like receptor binding potential and reduces adult age differences.
Smith CT, Crawford JL, Dang LC, Seaman KL, San Juan MD, Vijay A, Katz DT, Matuskey D, Cowan RL, Morris ED, Zald DH, Samanez-Larkin GR
(2017) J Cereb Blood Flow Metab : 271678X17737693
Show Abstract · Added March 21, 2018
The relatively modest spatial resolution of positron emission tomography (PET) increases the likelihood of partial volume effects such that binding potential (BP) may be underestimated. Given structural grey matter losses across adulthood, partial volume effects may be even more problematic in older age leading to overestimation of adult age differences. Here we examined the effects of partial volume correction (PVC) in two studies from different sites using different high-affinity D2-like radioligands (18 F-Fallypride, 11C-FLB457) and different PET camera resolutions (∼5 mm, 2.5 mm). Results across both data sets revealed that PVC increased estimated BPand reduced, though did not eliminate, age effects on BP. As expected, the effects of PVC were smaller in higher compared to lower resolution data. Analyses using uncorrected data that controlled for grey matter volume in each region of interest approximated PVC corrected data for some but not all regions. Overall, the findings suggest that PVC increases estimated BPin general and reduces adult age differences especially when using lower resolution cameras. The findings suggest that the past 30 years of research on dopamine receptor availability, for which very few studies use PVC, may overestimate effects of aging on dopamine receptor availability.
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2 Members
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0 MeSH Terms
Genome-wide association study to identify variants associated with acute severe vaso-occlusive pain in sickle cell anemia.
Chaturvedi S, Bhatnagar P, Bean CJ, Steinberg MH, Milton JN, Casella JF, Barron-Casella E, Arking DE, DeBaun MR
(2017) Blood 130: 686-688
MeSH Terms: Acute Pain, Adolescent, African Continental Ancestry Group, Anemia, Sickle Cell, Arterial Occlusive Diseases, Child, Child, Preschool, Chromosomes, Human, Pair 4, Epistasis, Genetic, Female, Fetal Hemoglobin, Genetic Variation, Genome-Wide Association Study, Genotyping Techniques, Humans, Male, Multicenter Studies as Topic, Polymorphism, Single Nucleotide, Prospective Studies
Added June 7, 2017
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19 MeSH Terms
Ventricular arrhythmias and sudden death in patients taking ibrutinib.
Lampson BL, Yu L, Glynn RJ, Barrientos JC, Jacobsen ED, Banerji V, Jones JA, Walewska R, Savage KJ, Michaud GF, Moslehi JJ, Brown JR
(2017) Blood 129: 2581-2584
MeSH Terms: Arrhythmias, Cardiac, Death, Sudden, Cardiac, Humans, Leukemia, Lymphocytic, Chronic, B-Cell, Male, Middle Aged, Pyrazoles, Pyrimidines
Added March 26, 2017
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8 MeSH Terms
Secondary benefit of maintaining normal transcranial Doppler velocities when using hydroxyurea for prevention of severe sickle cell anemia.
Ghafuri DL, Chaturvedi S, Rodeghier M, Stimpson SJ, McClain B, Byrd J, DeBaun MR
(2017) Pediatr Blood Cancer 64:
MeSH Terms: Adolescent, Anemia, Sickle Cell, Antisickling Agents, Blood Flow Velocity, Cerebrovascular Circulation, Child, Child, Preschool, Cohort Studies, Female, Humans, Hydroxyurea, Male, Retrospective Studies, Ultrasonography, Doppler, Transcranial
Show Abstract · Added January 2, 2017
In a retrospective cohort study, we tested the hypothesis that when prescribing hydroxyurea (HU) to children with sickle cell anemia (SCA) to prevent vaso-occlusive events, there will be a secondary benefit of maintaining low transcranial Doppler (TCD) velocity, measured by imaging technique (TCDi). HU was prescribed for 90.9% (110 of 120) of children with SCA ≥5 years of age and followed for a median of 4.4 years, with 70% (n = 77) receiving at least one TCDi evaluation after starting HU. No child prescribed HU had a conditional or abnormal TCDi measurement. HU initiation for disease severity prevention decreases the prevalence of abnormal TCDi velocities.
© 2016 Wiley Periodicals, Inc.
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14 MeSH Terms
Hemodynamic mechanisms underlying elevated oxygen extraction fraction (OEF) in moyamoya and sickle cell anemia patients.
Watchmaker JM, Juttukonda MR, Davis LT, Scott AO, Faraco CC, Gindville MC, Jordan LC, Cogswell PM, Jefferson AL, Kirshner HS, Donahue MJ
(2016) J Cereb Blood Flow Metab : 271678X16682509
Show Abstract · Added April 18, 2017
Moyamoya is a bilateral, complex cerebrovascular condition characterized by progressive non-atherosclerotic intracranial stenosis and collateral vessel formation. Moyamoya treatment focuses on restoring cerebral blood flow (CBF) through surgical revascularization, however stratifying patients for revascularization requires abilities to quantify how well parenchyma is compensating for arterial steno-occlusion. Globally elevated oxygen extraction fraction (OEF) secondary to CBF reduction may serve as a biomarker for tissue health in moyamoya patients, as suggested in patients with sickle cell anemia (SCA) and reduced oxygen carrying capacity. Here, OEF was measured (TRUST-MRI) to test the hypothesis that OEF is globally elevated in patients with moyamoya (n = 18) and SCA (n = 18) relative to age-matched controls (n = 43). Mechanisms underlying the hypothesized OEF increases were evaluated by performing sequential CBF-weighted, cerebrovascular reactivity (CVR)-weighted, and structural MRI. Patients were stratified by treatment and non-parametric tests applied to compare study variables (significance: two-sided P < 0.05). OEF was significantly elevated in moyamoya participants (interquartile range = 0.38-0.45) compared to controls (interquartile range = 0.29-0.38), similar to participants with SCA (interquartile range = 0.37-0.45). CBF was inversely correlated with OEF in moyamoya participants. Elevated OEF was only weakly related to reductions in CVR, consistent with basal CBF level, rather than vascular reserve capacity, being most closely associated with OEF.
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Distinct patterns of B-cell receptor signaling in non-Hodgkin lymphomas identified by single-cell profiling.
Myklebust JH, Brody J, Kohrt HE, Kolstad A, Czerwinski DK, Wälchli S, Green MR, Trøen G, Liestøl K, Beiske K, Houot R, Delabie J, Alizadeh AA, Irish JM, Levy R
(2017) Blood 129: 759-770
MeSH Terms: CD79 Antigens, Diagnosis, Differential, Flow Cytometry, Gene Expression Regulation, Neoplastic, Humans, Immunoglobulin M, Leukemia, Lymphocytic, Chronic, B-Cell, Lymphoma, Follicular, Lymphoma, Large B-Cell, Diffuse, Lymphoma, Mantle-Cell, Mitogen-Activated Protein Kinase 1, Mitogen-Activated Protein Kinase 3, Phospholipase C gamma, Phosphoproteins, Phosphorylation, Protein-Tyrosine Kinases, Proto-Oncogene Proteins c-akt, Receptors, Antigen, B-Cell, STAT1 Transcription Factor, STAT5 Transcription Factor, Signal Transduction, Single-Cell Analysis, Syk Kinase, p38 Mitogen-Activated Protein Kinases, src-Family Kinases
Show Abstract · Added December 31, 2016
Kinases downstream of B-cell antigen receptor (BCR) represent attractive targets for therapy in non-Hodgkin lymphoma (NHL). As clinical responses vary, improved knowledge regarding activation and regulation of BCR signaling in individual patients is needed. Here, using phosphospecific flow cytometry to obtain malignant B-cell signaling profiles from 95 patients representing 4 types of NHL revealed a striking contrast between chronic lymphocytic leukemia (CLL) and mantle cell lymphoma (MCL) tumors. Lymphoma cells from diffuse large B-cell lymphoma patients had high basal phosphorylation levels of most measured signaling nodes, whereas follicular lymphoma cells represented the opposite pattern with no or very low basal levels. MCL showed large interpatient variability in basal levels, and elevated levels for the phosphorylated forms of AKT, extracellular signal-regulated kinase, p38, STAT1, and STAT5 were associated with poor outcome. CLL tumors had elevated basal levels for the phosphorylated forms of BCR-signaling nodes (Src family tyrosine kinase, spleen tyrosine kinase [SYK], phospholipase Cγ), but had low α-BCR-induced signaling. This contrasted MCL tumors, where α-BCR-induced signaling was variable, but significantly potentiated as compared with the other types. Overexpression of CD79B, combined with a gating strategy whereby signaling output was directly quantified per cell as a function of CD79B levels, confirmed a direct relationship between surface CD79B, immunoglobulin M (IgM), and IgM-induced signaling levels. Furthermore, α-BCR-induced signaling strength was variable across patient samples and correlated with BCR subunit CD79B expression, but was inversely correlated with susceptibility to Bruton tyrosine kinase (BTK) and SYK inhibitors in MCL. These individual differences in BCR levels and signaling might relate to differences in therapy responses to BCR-pathway inhibitors.
© 2017 by The American Society of Hematology.
1 Communities
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25 MeSH Terms
Prolyl-4-hydroxylase 2 and 3 coregulate murine erythropoietin in brain pericytes.
Urrutia AA, Afzal A, Nelson J, Davidoff O, Gross KW, Haase VH
(2016) Blood 128: 2550-2560
MeSH Terms: Animals, Brain, Erythropoietin, Gene Expression Regulation, Hypoxia, Brain, Hypoxia-Inducible Factor-Proline Dioxygenases, Mice, Mice, Transgenic, Pericytes, Procollagen-Proline Dioxygenase, Transcription Factors, Transcription, Genetic
Show Abstract · Added September 30, 2016
A classic response to systemic hypoxia is the increased production of red blood cells due to hypoxia-inducible factor (HIF)-mediated induction of erythropoietin (EPO). EPO is a glycoprotein hormone that is essential for normal erythropoiesis and is predominantly synthesized by peritubular renal interstitial fibroblast-like cells, which express cellular markers characteristic of neuronal cells and pericytes. To investigate whether the ability to synthesize EPO is a general functional feature of pericytes, we used conditional gene targeting to examine the von Hippel-Lindau/prolyl-4-hydroxylase domain (PHD)/HIF axis in cell-expressing neural glial antigen 2, a known molecular marker of pericytes in multiple organs. We found that pericytes in the brain synthesized EPO in mice with genetic HIF activation and were capable of responding to systemic hypoxia with the induction of Epo. Using high-resolution multiplex in situ hybridization, we determined that brain pericytes represent an important cellular source of Epo in the hypoxic brain (up to 70% of all Epo-expressing cells). We furthermore determined that Epo transcription in brain pericytes was HIF-2 dependent and cocontrolled by PHD2 and PHD3, oxygen- and 2-oxoglutarate-dependent prolyl-4-hydroxylases that regulate HIF activity. In summary, our studies provide experimental evidence that pericytes in the brain have the ability to function as oxygen sensors and respond to hypoxia with EPO synthesis. Our findings furthermore suggest that the ability to synthesize EPO may represent a functional feature of pericytes in the brain and kidney.
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12 MeSH Terms
Blind men and the refractory ITP elephant.
Chaturvedi S, McCrae KR
(2016) Blood 128: 1537-8
MeSH Terms: Humans, Inosine Triphosphate, Purpura, Thrombocytopenic, Idiopathic
Added October 23, 2016
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3 MeSH Terms
Reduced-Intensity Conditioning with Fludarabine, Cyclophosphamide, and Rituximab Is Associated with Improved Outcomes Compared with Fludarabine and Busulfan after Allogeneic Stem Cell Transplantation for B Cell Malignancies.
Kennedy VE, Savani BN, Greer JP, Kassim AA, Engelhardt BG, Goodman SA, Sengsayadeth S, Chinratanalab W, Jagasia M
(2016) Biol Blood Marrow Transplant 22: 1801-1807
MeSH Terms: Adult, Aged, Antineoplastic Combined Chemotherapy Protocols, Busulfan, Calcineurin Inhibitors, Cyclophosphamide, Graft vs Host Disease, Hematopoietic Stem Cell Transplantation, Humans, Leukemia, B-Cell, Methotrexate, Middle Aged, Prognosis, Retrospective Studies, Rituximab, Survival Analysis, Transplantation Conditioning, Transplantation, Homologous, Vidarabine
Show Abstract · Added July 28, 2016
Reduced-intensity conditioning (RIC) has been used increasingly for allogeneic hematopoietic cell transplantation to minimize transplant-related mortality while maintaining the graft-versus-tumor effect. In B cell lymphoid malignancies, reduced-intensity regimens containing rituximab, an antiCD20 antibody, have been associated with favorable survival; however, the long-term outcomes of rituximab-containing versus nonrituximab-containing regimens for allogeneic hematopoietic cell transplantation in B cell lymphoid malignancies remain to be determined. We retrospectively analyzed 94 patients who received an allogeneic transplant for a B cell lymphoid malignancy. Of these, 33 received RIC with fludarabine, cyclophosphamide, and rituximab (FCR) and graft-versus-host disease (GVHD) prophylaxis with a calcineurin inhibitor and mini-methotrexate, and 61 received RIC with fludarabine and busulfan (FluBu) and GVHD prophylaxis with a calcineurin inhibitor and mycophenolate mofetil. The 2-year overall survival was superior in patients who received FCR versus FluBu (72.7% versus 54.1%, P = .031), and in multivariable analysis adjusted for Disease Risk Index and donor type, only the conditioning regimen (FluBu versus FCR: HR, 2.06; 95% CI, 1.04 to 4.08; P = .037) and Disease Risk Index (low versus intermediate/high: HR, .38; 95% CI, .17 to .86; P = .02) were independent predictors of overall survival. The 2-year cumulative incidence of chronic GVHD was lower in patients who received FCR versus FluBu (24.2% versus 51.7%, P = .01). There was no difference in rate of relapse/progression or acute GVHD. Our results demonstrate that the use of RIC with FCR and GVHD prophylaxis with a calcineurin inhibitor and mini-methotrexate is associated with decreased chronic GVHD and improved overall survival.
Copyright © 2016 The American Society for Blood and Marrow Transplantation. Published by Elsevier Inc. All rights reserved.
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19 MeSH Terms
Deep phenotyping of Tregs identifies an immune signature for idiopathic aplastic anemia and predicts response to treatment.
Kordasti S, Costantini B, Seidl T, Perez Abellan P, Martinez Llordella M, McLornan D, Diggins KE, Kulasekararaj A, Benfatto C, Feng X, Smith A, Mian SA, Melchiotti R, de Rinaldis E, Ellis R, Petrov N, Povoleri GA, Chung SS, Thomas NS, Farzaneh F, Irish JM, Heck S, Young NS, Marsh JC, Mufti GJ
(2016) Blood 128: 1193-205
MeSH Terms: Adult, Aged, Anemia, Aplastic, Female, Forkhead Transcription Factors, Humans, Immunologic Memory, Immunosuppression, Interleukin-2, Interleukin-7 Receptor alpha Subunit, Leukocyte Common Antigens, Male, Middle Aged, Receptors, CCR4, STAT5 Transcription Factor, T-Lymphocytes, Regulatory, fas Receptor
Show Abstract · Added June 10, 2016
Idiopathic aplastic anemia (AA) is an immune-mediated and serious form of bone marrow failure. Akin to other autoimmune diseases, we have previously shown that in AA regulatory T cells (Tregs) are reduced in number and function. The aim of this study was to further characterize Treg subpopulations in AA and investigate the potential correlation between specific Treg subsets and response to immunosuppressive therapy (IST) as well as their in vitro expandability for potential clinical use. Using mass cytometry and an unbiased multidimensional analytical approach, we identified 2 specific human Treg subpopulations (Treg A and Treg B) with distinct phenotypes, gene expression, expandability, and function. Treg B predominates in IST responder patients, has a memory/activated phenotype (with higher expression of CD95, CCR4, and CD45RO within FOXP3(hi), CD127(lo) Tregs), expresses the interleukin-2 (IL-2)/STAT5 pathway and cell-cycle commitment genes. Furthermore, in vitro-expanded Tregs become functional and take on the characteristics of Treg B. Collectively, this study identifies human Treg subpopulations that can be used as predictive biomarkers for response to IST in AA and potentially other autoimmune diseases. We also show that Tregs from AA patients are IL-2-sensitive and expandable in vitro, suggesting novel therapeutic approaches such as low-dose IL-2 therapy and/or expanded autologous Tregs and meriting further exploration.
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17 MeSH Terms