bluuebunny/crossref_metadata_2025_split huggingface dataset:
Vitamin D Deficiency Is Associated with Cardiac Iron Loading in Thalassemia Major.
Authors: Wood John C. , Claster Susan , Carson Susan , Rachna Khanna , Hofstra Thomas , Coates Thomas D. 
Published: October 2019

Abstract
Vitamin D deficiency is epidemic in the United States and is associated with decreased calcium absorption and metabolism, leading to bone loss, muscle weakness, and impaired pancreatic function. Many thalassemia major patients, as a result of decreases sunlight exposure and increased metabolic demand, are vitamin D deficient. We hypothesized that vitamin D deficiency might be associated with cardiac siderosis and impaired cardiac function through its modulation of calcium signaling in these patients. Methods: Permission for review of medical records was obtained from the Committee on Clinical Investigation at Children’s Hospital Los Angeles. We compared vitamin D25-0H and D1-25 levels in our thalassemia major patients with cardiac R2* (1/T2*) and left ventricular ejection fraction (LVEF) from the patient’s most recent cardiac MRI. Time difference between the exams was 2.8 ± 3.3 months with a range of 0.2 to 9.4 months. Other parameters recorded included age, gender, ferritin, liver iron (by MRI) and transferrin saturation. Univariate and multivariate regression was performed using JMP 5.1 (SAS, Cary, NC). Results: Twenty four patients had records suitable for review. There were 11 women and 13 men with a mean age of 14.7 ± 7.6 years [1.4 – 25.8]. Population was moderately iron overloaded with ferritin values of 2089 ± 1920 ng/ml [246 – 8230], liver iron 13.7 ± 11.4 mg/g dry wt [2–39.5], cardiac R2* 65 ± 61 Hz [19.8 – 229], and transferrin saturation 84 ± 18% [36%–106%]. Vitamin D25-OH levels were markedly depressed, 17.1 ± 8.5 pg/ml [1–33], with 13/24 values below the lower limit of 20 ng/ml. Surprisingly, vitamin D1-25OH levels were normal or elevated in all patients, 59.9 ± 19.5 pg/ml [32–103] with four patients exceeding the upper limit of normal of 71 pg/ml. There was no correlation between D25-0H and D1-25OH levels. D25-OH levels (but not D1-25OH levels) fell sharply with age (r2 = 0.48) and were negatively associated with liver iron (r2 = 0.20). Figures 1 and 2 demonstrated cardiac R2* and LVEF as functions of D25-OH levels. Cardiac R2* was log-linearly correlated with D25-OH level (r2 = 0.44, p=0.0001; levels below 13 ng/ml were associated with severe cardiac iron loading. Multivariate analysis of D25-OH, D1-25, HIC, ferritin, age, and transferrin saturation demonstrated that D25-0H and ferritin are the sole predictors of abnormal cardiac R2*, accounting for 38% and 5% of the variability respectively. LVEF was also negatively related to D25-OH levels (r2 = 0.35, p = 0.002). In multivariate analysis, vitamin D250H and vitamin D1-25OH levels accounted for 50% of the LVEF variability, independent of cardiac R2*. Conclusion Vitamin D deficiency is common in thalassemia major patients and strongly associated with cardiac iron uptake and ventricular dysfunction.
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Prevalence of T315I, Dasatinib-Specific Resistant Mutations (F317L, V299L, and T315A), and Nilotinib-Specific Resistant Mutations (P-loop and F359) at the Time of Imatinib Resistance in Chronic-Phase Chronic Myeloid Leukemia (CP-CML).
Authors: Deininger Michael W.N. , Mauro Michael J. , Matloub Yousif , Sinha Ritwik , Ploughman Lynn , Liu David , Radich Jerald 
Published: October 2019

Abstract
Mutations in the catalytic domain of ABL kinase (AKD) are a major mechanism of resistance to imatinib. Over 70 mutations in more than 50 amino acid residues have been reported to date. The ‘gatekeeper’ mutation, T315I, which causes complete resistance to all three FDA-approved tyrosine kinase inhibitors (TKIs), was reported to be not uncommon among a heterogeneous set of patients who had failed first-line imatinib therapy. In addition, the F317L, V299L, and T315A mutations were reported to convey a high degree of resistance to dasatinib, and higher frequency mutations within the P-loop (Y253H/F, E255V/K) and F359 mutations were associated with a high degree of resistance to nilotinib. We studied the prevalence of AKD mutations in the START-C phase II trial of dasatinib in patients who have failed imatinib (resistance or intolerance). Baseline mutation data were available for 95 of 99 patients with imatinib intolerance, and 274 of 288 patients with imatinib resistance. Of these patients, 13 (14%) with imatinib intolerance and 136 (50%) with imatinib resistance had AKD mutations. Of the 149 patients with mutations, only 3 (2%) had the T315I mutation. A total of 57 (38%) subjects had mutations in the P-loop (between 248–256): 13 patients with Y253H/F (9%), and 6 patients with E255V/K (4%). Four subjects (3%) had the F317L mutation, and 8 (5%) had F359 mutations. No subjects with V299L or T315A mutations were detected at baseline. The rates of complete cytogenetic response (CCyR) were 52% in patients with any mutation, 69% in patients with Y253H/F, 40% among those with E255V/K, 0% for T315I mutations, 0% for F317L mutations, and 50% for F359 mutations. Patients without mutations achieved a 55% rate of CCyR. These results confirm that select P-loop and F359 mutations are sensitive to dasatinib, while F317L and T315I mutations are resistant to dasatinib treatment. However, the overall incidence of these dasatinib-resistant mutants is low. In contrast, nilotinibresistant mutations in the P-loop (Y253H/F, E255V/K) or at F359 are more common, representing 15% and 5% of all patients with mutations, respectively. Therefore, the likelihood of harboring a nilotinib-resistant mutation at the time of imatinib resistance appears higher than the likelihood of harboring a dasatinib-resistant mutation, and suggests mutation testing may become instrumental for choosing between the various second-line TKI inhibitors to optimize outcomes.
Allelic Variation within the NKG2DL COMPLEX Influences Event Free Survival Following Stem Cell Transplantation.
Authors: Antoun Ayman , Briggs David , Jobson Shirley , Cook Mark , Moss Paul 
Published: October 2019

Abstract
NKG2D, an important activating receptor on NK cells, is capable of transmitting costimulatory signals by certain subsets of T cells. Viruses and tumours have evolved strategies to evade the NKG2D-mediated immune recognition thus illustrating the importance of NKG2D in mediating anti-tumour and anti-viral responses. Although NKG2D is a highly conserved molecule, it interacts with several structurally diverse ligands that are upregulated by cellular stress. The currently identified Ligands (NKG2DL) are the MHC class I-chain related proteins A and B (MICA and -B) and the ULBP/RAET1 families. MICA and MICB are structurally similar to MHC class I proteins, but share only 27% identity and do not associate with β2-microglobulin or bind peptides. MICA and MICB are very polymorphic with more than 50 MICA and 13 MICB alleles so far reported. Some of their alleles have been shown to be associated with auto-immune diseases such as Behcet’s disease and psoriasis vulgaris. Furthermore, there are currently six identified ULBPs and RAET genes, which are related to MHC class I in their α1 and α 2 domains, but lack the α3 domain and are located in a linked cluster on the long arm of chromosome 6. These proteins are closely related and polymorphic; however, the functional significance of this polymorphism remains unclear. We developed a novel polymerase chain reaction sequence specific primer (PCR-SSP) method for typing NKG2DL using genomic DNA and newly designed primers. First, we established the population genetics of 29 SNPs of NKG2DL, both in the promotor and coding regions in a control population of 223 Healthy controls and confirmed the presence of 24 of these SNPs. For our clinical studies we have limited the analysis to 10 NKG2DL SNPs with allele frequencies of at least 10%, which were used in subsequent analysis of association with clinical outcome of allogeneic stem cell transplantation. The allele and haplotype frequencies were determined in 211 patient and donor pairs who had undergone sibling stem cell transplantation (SSCT) for a range of diseases. Interestingly, a strong association between event free survival (EFS) and a specific SNP within this group of ligands was observed, which resulted in greater than a 25% difference in Event Free Survival at 6 years between its two allelic forms, (p=0.001). Initial analysis of the effect of matching of the SNPs between donor and recipient does not indicate any clear association with SSCT outcome. This is the first study of genetic variation within NKG2D ligands and effect on stem cell transplantation outcome and the findings of the significant associations of their SNPs with EFS indicates a critical role for the NKG2D-ligand interactions with transplant outcome.
Outcome of Patients with IgD and IgM Multiple Myeloma Undergoing Autologous Hematopoietic Stem Cell Transplants: A Retrospective CIBMTR Study.
Authors: Reece Donna E. , Vesole David H. , Shrestha Smriti , Dispenzieri Angela , Milone Gustavo , Peréz Waleska S. , Zhang Mei-Jie , Hari Parameswaran 
Published: October 2019

Abstract
Multiple Myeloma (MM) is the most common indication for autologous hematopoietic stem cell transplantation (auto HCT). However, little information is available regarding the outcome of patients (pts) with the rarer immunoglobulin subtypes IgD and IgM, which represent 2% and 0.5%, respectively, of all MM cases. In addition, IgD MM has been reported previously to have a poorer prognosis, at least after conventional therapy. The CIBMTR conducted a retrospective analysis of MM pts transplanted between 1995–2005 to describe the characteristics and results of auto HCT in IgD (n=36) and IgM (n=11) among 3578 MM patients with auto HCT during this period. Median follow-up of survivors was 41 (range 2–130) months for pts with IgD and 58 (range 5–101) months for those with IgM MM. Among pts with IgD subtype, median age was 52 years (yrs), 67% were male, 36% had a creatinine >2 mg/L, 61% had Durie-Salmon stage III disease at diagnosis and 33% had Kappa Serum Light chain; the corresponding values for IgM pts were 58 yrs, 36%, 73% and 55% respectively. Prior to auto HCT, 75% of IgD pts were chemosensitive and 25% had received >2 lines of chemotherapy, while all IgM pts were chemosensitive and none had received more than 2 lines of prior therapy. Median time from diagnosis to auto HCT was 9 months in both subtypes. The most common conditioning regimen was singleagent melphalan, and all but 1 pt with IgD disease were grafted with blood stem cells. The small sample size precluded multivariate analysis for potential prognostic factors for outcome. Below table summarizes the post-auto HCT results in these pts contrasted with a reference pool of IgG and IgA MM receiving auto HCT in the same time period.
Outcomes, probability (95% CI) IgD IgM IgG/IgA (n=36) (n=11) (n=1475) 100-day mortality, % 0 9 ( 0 – 32) 7 (5 – 8) Non MM deaths, % @ 1 yr 0 9 (0 – 32) 5 (4 – 7) @ 3 yrs 3 (0 – 13) 21 (2 – 51) 16 (14 – 18) Relapse/ Progression, % @ 1 yr 21 (9 – 37) 20 (2 – 49) 18 (16 – 20) @ 3 yrs 59 (41 – 76) 32 (8 – 64) 36 (34 – 39) Progression-free survival, % @ 1 yr 79 (63 – 91) 71 (41 – 93) 77 (74 – 79) @ 3 yrs 38 (21 – 56) 47 (17 – 78) 47 (44 – 50) Overall survival, % @ 1 yr 87 (74 – 97) 91 (68 – 100) 79 (77 – 85) @ 3 yrs 69 (51 – 84) 68 (36 – 93) 53 (50 – 57)
No striking differences are apparent in the post auto HCT outcomes of patients with IgD and IgM MM. These results are also consistent with published outcomes of pts with IgD/ IgM MM (Wechaleker et al Ann Hematol. 2005 Feb; 84(2):115–7; Maisner et al Bone Marrow Transplant. 2008 Jan; 41(1):51–4).
Dosing Patterns and Outcomes in African American, Asian, and Hispanic Patients with Heparin-Induced Thrombocytopenia Treated with Argatroban.
Authors: Hursting Marcie J , Jang Ik-Kyung 
Published: October 2019

Abstract
Nonwhites, as compared with whites, have increased risk for thromboembolic complications in heparin-induced thrombocytopenia (HIT) (Lewis et al, Chest 2006). To better characterize the risk in nonwhite patients, we retrospectively evaluated dosing patterns and clinical outcomes in African American, Asian, and Hispanic patients administered argatroban therapy for clinically diagnosed HIT. Patients were from previously reported, multicenter, prospective studies of argatroban therapy (2 mcg/kg/min, adjusted to achieve aPTTs 1.5–3 times baseline) in HIT (defined as an otherwise unexplained platelet count <100 x109/L, or 50% reduction in platelet count, following heparin therapy). For African American (n=52), Asian (n=13), and Hispanic (n=14) patient groups, baseline characteristics, therapeutic argatroban dose and duration, aPTTs during therapy, and clinical outcomes (death, including death due to thrombosis; amputation, including amputation secondary to ischemic complications of HIT; new thrombosis; and major bleeding within a 37-day period) were summarized and compared. Among groups, no differences were detected in demographic or baseline features, excepting weight (median values: 62, 77 and 85 kg, respectively, for Asians, African Americans, and Hispanics). Median baseline platelet counts were 45–71 x109/L, and approximately 50% of patients in each group had HIT-related thrombosis before argatroban was initiated. Each group received a similar duration of argatroban therapy (4.0–5.5 days), yet Asians needed a lesser dose (1.0 mcg/kg/ min, versus 1.9 mcg/kg/min in other groups) to achieve comparable aPTTs (61–69 s). New thrombosis occurred most often in African Americans (21%, versus 7–8% in other groups) and when baseline HIT-related thrombosis was present (9/13 events, 69%). Amputation occurred most often in Hispanics (21%, versus 0–12% in other groups) and when diabetes was present (6/9 events, 67%). Mortality was 21–31%, and mortality due to thrombosis was 0–7%. Asians had the lowest frequency of any thrombotic-related outcome (composite of death due to thrombosis, amputation secondary to ischemic complications of HIT, or new thrombosis: 8%, versus 27–29% in other groups). Two patients, each African American, experienced major bleeding (gastrointestinal), for an overall major bleeding rate of 2.5% and by-group rates of 0–4%. Although limited by small group sizes, our study is among the first to characterize outcomes in minority patients administered nonheparin therapy for HIT. Our findings suggest that, despite achieving comparable levels of anticoagulation with argatroban, African Americans and Hispanics are higher risk patients than Asians for poor outcomes in HIT and also that in minority patients with adverse outcomes, baseline HIT-related thrombosis or diabetes is often present.
Successful Harvesting of Peripheral Hematopoietic Stem Cells after Induction Treatment with Bortezomib, Adriamycin, Dexamethasone (PAD) in Patients with Newly Diagnosed Multiple Myeloma (MM)
Authors: Goldschmidt Hartmut , Lokhorst Henk M. , Bertsch Uta , van der Holt Bronno , Jarari Laila el , Salwender Hans-Jürgen , Zweegman Sonja , Vellenga Edo , Schubert Jörg , Blau Igor W. , Jie Asiong , Beverloo Berna , Hose Dirk , van de Velde Helgi , Schaafsma Martyn Ronald , Kersten Marie Jose , Delforge Michel , de Weerdt Okke , Van der Griend Rene , Wijermans Pierre , Martin Hans , Scheid Christof , Hänel Mathias , Schmidt-Wolf Ingo G.H. ,   Pieter Sonneveld for the HOVON GMMG group
Published: October 2019

Abstract
The HOVON-65/GMMG-HD4 trial is a prospective, randomized phase III trial to evaluate the efficacy of bortezomib prior to high-dose melphalan (200 mg/m2, HDM) on response and progression-free survival (PFS) in patients with newly diagnosed MM stage II or III according to Salmon & Durie (SD). Until May 2008 in total 833 patients aged 18–65 years were included in the trial. Patients were randomized to receive three cycles of VAD (arm A; vincristin 0,4mg, days 1–4, adriamycin 9 mg/m2, days 1–4, dexamethasone 40 mg, days 1–4, 9–12, and 17–20) or PAD (arm B; bortezomib 1.3 mg/m2, days 1,4,8,11, adriamycin 9 mg/m2, days 1–4, dexamethasone 40 mg, days 1–4, 9–12, and 17–20). Hematopoietic stem cells were mobilized in patients using the CAD regimen (cyclophosphamide 1000 mg/m2 iv day 1, adriamycin 15mg/m2, days 1–4, dexamethasone 40mg, days 1–4) and G-CSF. After stem cell harvesting all patients received one or two cycles of HDM with autologous stem cell transplantation followed by maintenance therapy with thalidomide 50 mg daily (arm A) and bortezomib 1.3 mg/m2 once every 2 weeks (arm B), respectively.
As of August 2008 stem cell harvesting data from the first consecutively enrolled 150 patients (75 per arm) were analyzed. The data of the initial 300 patients (150 per arm) will be available by November 2008. Both treatment arms did not differ in age, SD stage of disease, ISS stage, and FISH abnormalities. 132 patients (88%) were treated with CAD plus G-CSF. Dosing and type of G-CSF treatment were comparable in both arms.
In all patients stem cell collection was successful and at least two autografts could be harvested (minimal number of stem cells permitted per autograft was 2.0 ×106 CD 34+ cells per kg BW).
Induction treatment Days until first leukapheresis Median (range) Number of leukaphereses Median (range) Number of harvested CD34+ stem cells (× 106) per kg BW Median (range) PAD 110 (96–149) 1 (1–4) 10.5 (4.1–37.6) VAD 111 (95–156) 1 (1–5) 9.3 (4.0–37.0)
In 64% of the patients in arm A (VAD) and 79% of the patients in arm B (PAD) only one leukapheresis was sufficient for stem cell harvesting. In all patients hematopoietic reconstitution was achieved after HDM followed by autografts harvested after PAD or VAD. We conclude that stem cell harvesting after PAD is very well feasible.
The Role of C5a in the Mobilization of Hematopoietic Stem/Progenitor Cells
Authors: Jalili Ali , Shirvaikar Neeta , Korol Chris , Janowska-Wieczorek Anna 
Published: October 2019

Abstract
The complement system, a vital component of the immune system, has been shown to play a role in hematopoietic stem/progenitor cell (HSPC) trafficking. C3a is known to be important in the retention of HSPC in the bone marrow (BM) as C3a-deficient mice are good mobilizers, and C5a is important in the mobilization of HSPC because C5a-deficient mice are poor mobilizers (Stem Cells2007; 25: 3093). Further, granulocyte-colony stimulating factor (G-CSF) activates the complement system via the classical pathway, down-regulates stromal-derived factor (SDF)-1 in BM stromal cells and decreases expression of its receptor, CXCR4, in myeloid cells. In this work investigated the mechanism of C5a involvement in HSPC mobilization. Using RT-PCR and FACS we examined the expression of the C5a receptor (CD88) on mobilized peripheral blood (PB) and steady-state PB HSPC and mature white blood cells, and in vitro-expanded myeloid, erythroid, and megakaryocytic progenitor cells. We found that
CD88, like the G-CSF receptor, is not expressed on BM, PB or cord blood HSPC (CD34+ cells); during CD34+ cell differentiation the expression of CD88 increases in myelocytic and megakaryocytic progenitors; and the percentage of monocytes and polymorphonuclear (PMN) cells expressing CD88 is significantly higher in mobilized than in steady-state PB.
Examing the function of C5a (using flow cytometry) we found that, unlike C3a, C5a decreases CXCR4 expression in a dose-dependent manner in monocytes and PMN, but not in lymphocytes; and this effect was not seen when anti-C5a antibody was added. Interestingly, we found that G-CSF down-regulation of CXCR4 expression on PMN was partially restored by anti-C5a antibody, suggesting that the mobilizing effects of G-CSF are at least in part due to the action of C5a. Moreover, chemotaxis of PMN towards SDF-1 (chemotaxis assay) increased when these cells were stimulated with C3a but decreased with both C5a and G-CSF, reflecting the CXCR4 expression status of these cells after stimulation. We also examined the effect of C5a on matrix metalloproteinase (MMP) secretion in BM leukocytes and found that, like G-CSF, C5a increased MMP-9 and MMP-2 secretion into media (zymography). Since the SDF-1/CXCR4 axis plays an integral role in the retention of HSPC in the BM, we conclude that C5a promotes mobilization by disrupting this axis, as well as increasing MMP-9 and MMP-2 secretion by BM leukocytes, thereby allowing egress of HSPC into the PB.
Development of a Limiting Dilution Assay and MHC-Matched Transplantation Model to Detect Hematopoietic Stem Cell Activity in Zebrafish
Authors: de Jong Jill L. O. , Burns Caroline E. , Tinmaung Aye , Pugach Emily , Mayhall Elizabeth , Smith Alexandra C.H. , Feldman Henry A. , Zhou Yi , Zon Leonard I. 
Published: October 2019

Abstract
The zebrafish is a powerful model for the discovery of novel genetic mechanisms through large scale forward and reverse screening methodologies, and has been used prominently for the study of hematopoiesis. Methodologies capable of assessing hematopoietic stem cell (HSC) activity, however, are largely undeveloped. Here, we created a long-term limit dilution hematopoietic reconstitution assay in adult zebrafish, defined zebrafish haplotypes at the proposed core Major Histocompatibility Complex (MHC) locus, and tested their functional significance by performing the first matched and unmatched transplants. We identified a sublethal radiation dose of 25Gy which was optimal for hematopoietic reconstitution while minimizing mortality presumably due to radiation damage of other organs. Our method detects multi-lineage repopulation in primary and secondary recipients. Using Poisson statistics, our limit dilution analyses suggest that at least 1 in 65,000 nucleated marrow cells in zebrafish contain repopulating activity, consistent with mammalian marrow HSC frequency. Finally, we characterized the genes in the proposed MHC core locus on chromosome 19 for one family used for sibling marrow transplantations. We were able to identify the four parental MHC haplotypes by sequencing PCR products amplified for specific MHC Class I genes: mhc1uea, mhc1ufa, mhc1uda, mhc1uba, mhc1uca, loc751750, and mhc1uxa2. F1 generation siblings were subsequently typed, and we demonstrated that matching the donor and recipient MHC haplotypes at this chromosome 19 locus dramatically increases engraftment and percentage of donor chimerism in recipients compared to MHC-mismatched donors and recipients. At 15 weeks post-transplant, MHC-matched recipients showed engraftment in 4 of 5 surviving fish with mean donor chimerism of 59.15% +/− 25.1% for myeloid cells and 8.26% +/− 6.2% for lymphoid cells. Those animals receiving MHC-mismatched donor marrow had only 3.92% +/− 2.1% myeloid donor chimerism and 0.97% +/− 0.5% lymphoid donor chimerism. These data represent the first assay allowing long term HSCs to be distinguished from other hematopoietic progenitor fates and provides the first functional test of MHC genes between zebrafish haplotypes. This method opens the door to MHC-matched long-term transplantation experiments in zebrafish that have previously not been possible, including competitive transplantation experiments with zebrafish mutants already identified in prior genetic screens, and long-term tumor transplantation assays. By harnessing the unique genetic and screening advantages of the zebrafish model, such experiments may provide critical insight into mammalian transplantation biology.