bluuebunny/crossref_metadata_2025_split huggingface dataset:
Serum Proteomic Profiling and Study of Haptoglobin Polymorphisms in Patients with Chronic GVHD after Allogeneic Hematopoietic Stem Cell Transplantation.
Authors: McGuirk Joseph P. , Yan Ying , Gang Hao , Hou Weijian , Abhyankar Sunil , Williams Casey , Belt Robert , Ruan Jianpa , Yan Weisi , Wieman Jeffery 
Published: October 2019

Abstract
We studied serum proteomic profiling in an attempt to discover novel biomarkers in the setting of clinically manifest graft versus host disease (GVHD) after allogeneic hematopoietic cell transplantation (Allo-HCT) by two-dimension gel electrophoresis (2-DE) and mass spectrometry analysis. More than 1000 protein spots per gel could be detected in individual samples and the distribution patterns of these spots differed significantly between the samples collected pre- and post- chronic GVHD (cGVHD) in the same patients. Mass spectrometric analysis in the paired 2DE gels from individual patients pre- and post-GVHD were performed. A group of proteins, Haptoglobin (Hp), Alpha-1-antitrypsin, Apolipoprotein A-IV, Serum paraoxonase and Zn-alpha-glycoprotein were demonstrated to be up-regulated and the proteins, Clusterin precursor, Alpha-2-macroglobulin, Serum amyloid protein precursor, Sex hormone-binding globulin, Serotransferrin and Complement C4 were found to be down-regulated in the patients with extensive cGVHD. Serum Hp was significantly increased in most patients following the development of cGVHD; Hp has been demonstrated to serve as an immuno-modulatory acute phase protein and may involve T- cell activation; further, Hp specific phenotypes have defined roles in influencing the pathophysiology of several immune system disorders. For these reasons, we used immunoblotting and PCR in combination with 2-DE gel image analysis to determine Hp polymorphisms in 24 allo-HCT patients (14 chronic GVHD, 4 acute GVHD and 6 without GVHD) and 10 normal donors. The results demonstrate that patients with cGVHD had a higher incidence of HP 2-2 phenotype (50.0%), in comparison to the patients without cGVHD (0%) and normal donors (10%) (Table 1), suggesting that the specific Hp polymorphism may play a role in the development of cGVHD after allo-HCT. A prospective analysis of Hp phenotype and the subsequent development of cGVHD is now being planned. This limited analysis suggests that proteomic profiling may provide significant contributions not only for identification of novel prognostic biomarkers, but also for novel insights into the pathophysiologic mechanisms of GVHD in allo-HCT.
HP Phenotype Patients 1-1 2-1 2-2 Chronic GVHD n=14 2(14.3%) 5(35.7%) 7(50.0%) Acute GVHD n=4 0 3 1 no GVHD n=6 1(16.7%) 5 (83.3%) 0 Normal Donor n=10 1(10.0%) 8(80.0%) 1(10.0%)
Impact of gamma/delta TCR+, Foxp3+ and Toll-Like Receptor Expressing T-Cells on the Outcome of Patients Receiving Unrelated Peripheral Blood Stem Cell Transplantation.
Authors: Platzbecker Uwe , Pabst Caroline , Schirutschke Holger , Wagner Ines , Theuser Cathrin , Ehninger Gerhard , Bornhauser Martin 
Published: October 2019

Abstract
Introduction: The role of gamma/delta (GD), foxp3 (regulatory, TREGs) and Toll-like receptor (TLR) expressing T-cells contained in the graft for the induction of graft versus host disease (GVHD) in patients after unrelated peripheral blood stem cell transplantation (PBSCT) is unknown.
Methods and patients: We therefore determined by flowcytometry and PCR the content of these T-cell subsets within the graft of 63 patients with hematological malignancies receiving unrelated PBSCT followed by cyclosporine A and methotrexate as GVHD prophylaxis and correlated these data with clinical endpoints. Patient and donor pairs were matched at least in nine out of ten characteristics (n=17), whereas a complete match (10 out of 10) was observed in 46 (73%) patients.
Results: The grafts contained a median of 11.25 x 106/kg (2.7–33.5) CD4+foxp3 T-cells and 9.79 x 106/kg (1.4–36.2) GD T-cells. Patients receiving lower amounts of CD4+foxp3+ cells had an increased risk of acute GVHD II–IV (65% vs. 44%, p=0.03). Whereas the overall CD3+ cell dose was not associated with the incidence of GVHD, increased counts of gdTCR expressing CD3+ cells showed significant correlation with an increased risk of GVHD II–IV (66% vs. 40%, p=0.028). A lower CD34+ cell dose was also significantly associated with an increased risk of GVHD II–IV (63% vs. 38%, p=0.04). Interestingly, there was a positive correlation between CD34+ and CD4+foxp3 cell dose (r=0.34, p=0.007).
In contrast to the blood of healthy donors, TLR2 and 4 were both expressed on up to 11 % of CD4+ and CD8+ cells within the graft but had no influence on the severity of GVHD. Interestingly, a higher expression of TLR2 and 4 on CD4+ but not CD8+ T-cells was associated with a higher treatment-related mortality (CD4: 17% for TLR2low vs. 45% for TLR2high, 13% for TLR4low vs. 52% for TLR4high, p=0.002).
Conclusion: Strategies aiming at selective manipulation of graft composition or add-back of distinct T-cell subsets after unrelated PBSCT might be a promising strategy in order to modulate the extent of clinical GVHD. Furthermore, up-regulation of TLR2 and 4 on T-cells and their role for non-relapse mortality warrants further investigation.
Translational Regulation of Gene Expression by the NPM-ALK Fusion Kinase of Anaplastic Large Cell Lymphoma: A Global Evaluation of Differentially Recruited mRNA’s to Polyribosomes.
Authors: Funato Kotaro , Haq Naznin , Sun Yezhou , Chen Jin , Khitrov Greg , Zhang Weijia , Sternberg David W. 
Published: October 2019

Abstract
The NPM-ALK fusion tyrosine kinase generated by the t(2;5)(p23;q35) chromosomal translocation is present in approximately 50% of anaplastic large cell lymphomas. NPM-ALK is known to play a causal role in the generation of hematopoietic neoplasia, and it has multiple potential sites of tyrosine phosphorylation that can bind to signaling effector molecules. We found that expression of NPM-ALK regulates mediators of translational initiation, including mTOR, S6K1, and 4E-BP1. Moreover, other investigators have shown that expression of proteins that mediate the control of translational initiation can be rate-limiting in the pathogenesis of neoplasia. Collectively, these findings stimulated our hypothesis that NPM-ALK promotes neoplasia by altering the partitioning of specific mRNA’s to polysomes and thereby regulating their translation. To evaluate this hypothesis, we assessed the global profile of polysomal mRNA in cells that express the NPM-ALK fusion kinase.
In this study, we generated Ba/F3 murine hematopoietic cells that express kinase-active NPM-ALK or a kinase-deficient NPM-ALK mutant (K210A). Cells were maintained in the presence of the cytokine IL-3 to minimize changes secondary to cell cycle redistribution or early apoptosis. We used these cell lines to compare in a global manner the partitioning of mRNA species to polysomes. We isolated polyribosome preparations using conventional sucrose gradient fractionation, and from this purified polysomal material we extracted mRNA. Similarly, we prepared total mRNA from these cell lines. The global profile of gene expression for both total and polysomal RNA was assessed using Affymetrix mouse genome microarrays. The data generated in this effort were analyzed using the GeneChip robust multichip analysis (GCRMA) method. Significance Analysis of Microarrays (SAM) and Linear Models for Microarray Data (Limma) were employed to identify significantly differentially expressed genes. By culturing each cell line in the presence of IL-3, we found little difference in total cellular mRNA levels. However, we found that expression of kinase-active NPM-ALK markedly altered the partitioning of mRNA’s to the polysomal pool. We identified 286 genes whose mRNA’s exhibited altered polysomal partitioning, including 102 decreased in cells with kinase-active NPM-ALK and 184 with increased polysome association. These translationally regulated mRNA’s encode proteins associated with transcriptional control, post-translational modification of proteins, and hematopoietic neoplasia. Our findings support the assertion that NPM-ALK signaling regulates gene expression in part through translational control. We speculate that concerted dysregulation of transcription and translation by oncogenes might broadly mediate the pathogenesis of hematopoietic neoplasia.
The Effect of Donor CD4+CD25+ Regulatory T Cells on Hematopoietic and Immune Reconstitution, GVHD and Disease-Free Survival after Allogeneic Hematopoietic Stem Cell Transplantation.
Authors: Yang Kai , Liu Qifa , Fan Zhiping , Sun Jing , Yi Zhengshan 
Published: October 2019

Abstract
Objectives To explore the effect of donor CD4+CD25+ regulatory T cells (TReg) on hematopoietic reconstitution, immune reconstitutuion and GVHD in patients who received allogeneic hematopoietic stem cell transplantation (allo-HSCT).
Methods 30 patients were divided into high TReg cell group (TReg≥10.0×106 cells/kg) and low TReg cell group (TReg<10.0×106 cells/kg) according to the number of TReg cells in the grafts. 13 patients were in high TReg cell group and 17 in low TReg cell group. The patients details of the two groups are in the following table. Flow cytometry (FCM) was used to continuously detect the percentage of TReg cells in the graft, T lymphocyte subsets and TReg cells in the recipients’ peripheral blood at different time after allo-HSCT. The hematopoietic reconstitution, immune reconstitution, TReg cell reconstitution, the incidence of GVHD and the disease-free survival were observed in the two groups.
Results The reconstitution of WBC and plantelet of high TReg cell group and low TReg cell group were 8.62±2.293 and 8.88±2.713, 12.69±5.736 and 15.18±16.708 days, respectively, and differed little between the two groups (P value was 0.778, 0.613, respectively). The incidence of acute GVHD (aGVHD) in high TReg cell group (15.38%) was obviously lower than that in low TReg cell group (58.82%) (P=0.016). There was significantly negative correlation (r=−0.382, P=0.037) between the number of infused donor TReg cells and severity of aGVHD. The reconstitution of CD4+CD3+T, CD45RO+CD4+T cells at 15 days and CD3+T, CD4+CD3+T cells at 30 days in high TReg cell group were notably faster than those in low TReg cell group after allo-HSCT (P value was 0.039, 0.024, 0.014, 0.020, respectively). The reconstitution of TReg cells at 15 and 180 days were significantly faster than those in low TReg cell group after allo-HSCT (P value was 0.013, 0.005, respectively). The 2-year disease-free survival of high TReg cell group and low TReg cell group were (69.90±15.50)% and (85.60±9.50)%, respectively, and there were no significantly difference between the two groups (P=0.514).
Conclusion TReg cells could contribute to decreasing the incidence of aGVHD, promoting immune reconstitution and TReg cells reconstitution.
Cyclosporin A Kinetics in Children after Stem Cell Transplantation.
Authors: Willemze Annemieke J. , Cremers Serge C. , Schoemaker Rik C. , Lankester Arjan C. , den Hartigh Jan , Burggraaf Koos , Egeler Maarten , Vossen Jaak M. 
Published: October 2019

Abstract
Introduction and aim of study. Cyclosporin A (CsA) is commonly used as prophylaxis against Graft versus Host disease (GVHD) after allogeneic haematopoietic stem cell transplantation (SCT). Therapeutic drug monitoring is necessary because of its unpredictable absorption and narrow therapeutic window. Usually dose adjustments are based on trough levels, although these correlate poorly with CsA systemic exposure in adults. The aim of this study was to investigate intravenous and oral CsA pharmacokinetics in children after SCT and to develop a limited sampling strategy in order to determine CsA systemic exposure.
Methods. Pharmacokinetics was investigated in children, aged 1.8 to 16.1 yrs, 2 to 43 days after stem cell infusion (median: 25 days), after intravenous or oral administration of CsA in, respectively, 9 and 8 children. Parameter estimation was performed using nonlinear mixed effect modeling as implemented in the NONMEM program.
Results and conclusions. Pharmacokinetics were described adequately with a two-compartment model with lag time (population estimates: Cl=10.5 l/h; Vc=15.5 L; Vp=60.6L; t ½ absorption=1.01 h, Tlag=0.6 h). Combination of Cthrough and a Bayesian fitting procedure with the pharmacokinetic model can adequately estimate the systemic exposure to CsA (r2=0.90, Figure 1). The estimation of actual AUC improves when more concentration time-points are used. No relation between body weight and clearance was found (Figure 2). Based on these data, CsA should not be dosed per kilogram body weight. A regimen with a fixed dose for all, adjusted on through levels in combination with the described pharmacokinetic model, may be more appropriate. (open circles: oral administration; closed circles: intravenous administration)
Figure Figure Figure Figure
Treosulfan, Fludarabine, and Antithymocyte Globulin - A Low Toxicity Conditioning Regimen for Unrelated Donor - Hematopoietic Stem Cell Transplantation in Chronic Myeloid Leukemia.
Authors: Holowiecki Jerzy , Giebel Sebastian , Wojnar Jerzy , Markiewicz Miroslaw , Holowiecka-Goral Aleksandra , Wylezol Iwona , Krawczyk-Kulis Malgorzata , Wozniczka Krzysztof 
Published: October 2019

Abstract
Unrelated donor - hematopoietic stem cell transplantation (URD-HSCT) is the treatment of proved long-term efficacy for chronic myeloid leukemia (CML) patients not having an HLA-identical sibling. However, high procedure-related toxicity observed after oral busulfan- or TBI-based conditioning limits its applicability and deteriorates outcome [Radich, Blood2003, 102, 31–5]. This is of increasing importance in the presence of challanging options offered by tyrosine kinase inhibitors. Between 2003–2006 we introduced a new preparetive regimen consisting of Treosulfan (a soluble alkylyting agent) 14 g/m2/d on days -6, -5, -4, Fludarabine 30 mg/m2/d on days -6, -5, -4, -3, -2, and, anti-thymocyte globulin (ATG) at a total dose of 6 mg/kg.
Thirty patients (age 32, range 16–48 years) with CML in the 1st chronic phase (n=29) or in 2nd chronic phase (n=1) were included in the study. Median interval from diagnosis to alloHSCT equaled 1.0 (0.5–12.0) years. 63% of patients had previously been treated with Imatinib. The donors were selected based on high resolution typing for both HLA class I and II. 43% of donors were mismatched for a single HLA-C (n=9), HLA-DQB1 (n=3) or HLA-B locus (n=1). Bone marrow was used a source of stem cells in 19 patients, peripheral blood - in 11 cases. GVHD prophylaxis consisted of Cyclosporin A and short-course Methotrexate.
All patients engrafted with the median time to neutrophil recovery >0.5 G/L and PLT >50 G/L of 19 (10–30) days and 18 (12–29) days, respectively. Complete donor chimerism was achieved until day +100 in all but one patient. Grade 3–4 neutropenic infections occurred in 13% of patients. Grade 3–4 mucositis as well as hepatic toxicity including VOD were not observed. The incidence of grade II acute GVHD was 23%, whereas grade III-IV acute GVHD was not observed. The incidence of extensive chronic GVHD was 10%.
At 3 years the probability of the overall survival and hematological relapse-free survival equaled 82% (+/−7%). The cumulative incidence of non-relapse moratlity was 18% (+/−7%) (fungal infection n=3, bacterial infection n=1, EBV-LPD n=1). Four patients required donor lymphocyte infusion or additional interferon or imatinib treatment because of incomplete donor chimerism or molecular/cytogenetic relapse after initial response.
We conclude that treosulfan + fludarabine + ATG conditioning is associated with low organ toxicity, low incidence of severe GVHD and NRM. The regimen is feasible option for CML patients referred for URD-HSCT in tyrosine kinase inhibitors era.
Pulmonary Changes in Myeloma Patients Following High Dose Melphalan.
Authors: Ford Clyde , Jensen Robert E. , Asch Julie , Pearl James E. , Crapo Robert O. , Petersen Finn 
Published: October 2019

Abstract
Background: Eligibility for high dose chemotherapy and autologous stem cell rescue often includes adequate pulmonary function. While high dose melphalan has been noted to cause significant pulmonary toxicity in a small percentage of patients with adequate pulmonary function, there are little published data on risk factors and use in lung impaired patients. We retrospectively reviewed the charts of 50 patients with myeloma who received a fixed dose of melphalan (200 mg/m2) and who had pre-melphalan and at least one post-melphalan spirometry (FVC and FEV1) and diffusing capacity (DLco) measurement. Comparisons were made with Pearson correlations and one-way ANOVA. Patients receiving melphalan showed no significant differences in mean FVC (p=0.40), FEV1 (p=0.48) or hemoglobin corrected DLco (p=0.40) comparing baseline to 3-month and 1-year results with 1-way ANOVA. There was a consistent increase in mean FVC(L), FEV1(L) and DLco (ml CO/min/mmHg) from pre to 3 months post (3m) and to one-year post (1y): FVC: pre=3.89, 3m= 4.02, 1y=4.24; FEV1: pre=2.92, 3m=2.95, 1y=3.14; DLco: pre=24.3, 3m=25.1, 1y=26.5. However, individual changes in DLco showed a wide distribution. Therefore, we examined a number of potential risk factors for change in DLco at 3 months. No detrimental effects were discernable for age, gender, history of prior pulmonary disease including smoking, pre-melphalan lung function, the use of high dose cyclophosphamide in the mobilization regimen, amount of prior chemotherapy or chest radiation, disease stage or response, or renal function. CD34+ cell dose (p=0.017, r = −0.344) and immunoglobulin type (IgA worse than IgG) (p=0.029, r = 0.316) were correlated and were independent factors on regression analysis (p<0.0018, r2=0.36). We conclude that on average, high dose melphalan produces little pulmonary toxicity and may be considered for selected patients with impaired baseline pulmonary function. It may be of value to avoid higher CD34+ cell doses in patients with a low pre-melphalan DLco. More work should be directed at identifying the factors that contribute to pulmonary function compromise following high dose regimens.
Prognostic Factors in the UK LRF CLL4 Trial.
Authors: Oscier David Graham , Wade Rachel , Orchard Jenny , Davis Zadie , Best Giles , Morilla Alison , Brito-Bapapulle Vasantha , Matutes Estella , Richards Sue , Catovsky Daniel 
Published: October 2019

Abstract
The LRF CLL4 trial randomised 777 previously untreated patients with Binet stage progressive A, B or C disease between January 1999 and October 2004 to receive either Chlorambucil, Fludarabine or Fludarabine and Cyclophosphamide. Interphase FISH for deletions of chromosome 6q, 11q, 13q, 17p and trisomy 12, IgVH gene mutational status (98% cut off), CD38 (7% cut off) and ZAP70 (10% cut off) expression were measured at randomisation on 579, 523, 535 and 478 patients respectively. Leukemic cells from 39 patients utilised the VH3-21 gene of whom 33 had homologous CDR3’s. Among the biological markers, log rank analysis showed that >20% p53 loss, del 11q, unmutated VH genes, high CD38 and high ZAP 70 correlated with disease progression or death (Table 1) but not deletion of chromosome 6q, 13q and trisomy 12 (p=0.7, 0.3 and 0.2 respectively). There was no difference in PFS or response duration between the 52 patients with 5–20% p53 loss and the 494 patients with no p53 loss. Multivariate Cox regression analysis showed that >20% p53 loss (p<0.0001), unmutated IgVH genes (p=0.0001), deletion of 11q (p=0.02) and male gender (p=0.03) were independent risk factors for short PFS. The effects of stage and age were overridden by FISH abnormalities. High ZAP70 expression was only significant when VH gene mutation status was not included in the model. CD38 expression was only significant in univariate analysis.
Table 1 Variable Progression or Death/N Univariate p-value(log rank test) Gender Male 384/573 0.002 Female 111/204 17q(p53) No 131/546 <0.00005 Yes 21/33 IgVH Unmutated 105/203 <0.00005 Mutated 225/320 del 11q No 288/463 <0.00005 Yes 87/116 ZAP70 Negative 140/242 0.003 Positive 158/236 CD38 Negative 110/201 0.0001 Positive 227/334
Among the 320 unmutated cases there was no significant difference in PFS between those with 100% homology (227 cases) and those with 99% or 98% homology to the germline sequence (93 cases). Mutated VH3-21 cases were more likely to express ZAP70 than other mutated cases, p=0.004. Excluding patients with >20% p53 loss, patients using the VH3-21 gene had similar progression free survival (PFS) to those remaining patients with unmutated VH genes and an inferior PFS to those with mutated VH genes (2p=0.0001). The adverse prognostic significance of 11q deletions was not clearly evident in an interim analysis presented at ASH ‘05. Patients can now be divided into 3 risk groups (Table 2). This risk stratification provides the basis of evaluating differing treatment modalities for each risk group in subsequent clinical trials.
Table 2 Risk Group Definition Progression or Death/N Univariate p-value (log-rank test) 3 yr PFS Poor >20%p53 loss 28/33 0% Standard Unmutated VH or 11q deletion or VH3-21 208/292 <0.00001 24.7% Good Mutated VH(excl VH3–21) 79/161 55.0%