bluuebunny/crossref_metadata_2025_split huggingface dataset:
Characteristics of Chronic-Phase CML Patients Having Durable Cytogenetic Response to Low-Dose Imatinib
Authors: Kawaguchi Tatsuya , Hamada Akinobu , Nakashima Reiko , Horikawa Kentaro , Ishihara Sonoko , Saito Hideyuki , Mitsuya Hiroaki 
Published: April 2020

Abstract
Imatinib mesylate (IM), a BCR-ABL tyrosine kinase inhibitor, has been established as first-line treatment of chronic-phase chronic myeloid leukemia (CML). On the basis of the IRIS study, 400mg/day IM has been recommended as an initial dose for adult CML patients. Although most patients usually tolerate the recommended dose, serious adverse effects such as grade 3 or 4 cytopenia may occur and require dose reduction of IM to 200–300mg/day. In fact, 8% of patients were receiving less than 400mg IM during 5-year follow-up in the IRIS study (Druker et al, New Engl J Med, 2006). In clinical settings, low-dose IM is actually effective for some patients; however, clinical and laboratory features of such patients have not been well investigated. Recently, it was demonstrated that the effective plasma threshold for trough IM levels should be maintained above 1,002 ng/ml to obtain maximal effects in CML patients (Picard et al, Blood, 2007). In this regard, determination of trough IM plasma levels may help to predict efficacy of low-dose IM. To evaluate the association of optimal IM doses with trough IM levels and patients’ basic characteristics such as body surface area (BSA), we assessed trough plasma concentrations of IM using high performance liquid chromatography (Hamada et al, J Pharmacol Exp Ther, 2003) in 31 chronic-phase CML patients, who were treated in Kumamoto University Hospital during 2003 to 2007. An optimal dose of IM was determined by a favorable response to IM achieving complete cytogenetic response and tolerable adverse events. Twenty-seven patients tolerated IM therapy during the observation period: optimal doses of IM were 400mg/day in 13 patients, 300mg/day in 9 patients, and 500 or 600 mg/day in 5 patients. Four patients discontinued IM for some reasons: two for toxicity, one for a concomitant unrelated disease and one for inefficacy due to drug-resistance. The trough plasma concentrations of IM were 1.64±0.68 μg/ml (mean±SD) in patients on the standard dose of 400mg/day IM (standard dose group) and 1.38±0.53 μg/ml in patients on the reduced dose of 300mg/day IM as an optimal dose (reduced dose group). Both mean trough levels of two groups showed no significant difference and exceeded the effective plasma threshold. Interestingly, BSA was significantly smaller in patients of the reduced dose group than those of the standard dose group (1.50± 0.16 vs. 1.75 ± 0.15 m2 (mean± SD), p=0.001). An optimal IM dose was found to be significantly associated with age and gender as well as BSA. These results suggest that the reduced dose of 300mg/day IM may be sufficient for the treatment of CML patients with smaller body sizes. Monitoring of trough IM levels should enable proper management of individual patients in combination with regular monitoring of optimal response to IM.
Processing of Hemojuvelin Requires Retrograde Trafficking to the Golgi in HepG2 Cells.
Authors: Zhang An-Sheng , Maxson Julia Julia , Enns Caroline A 
Published: April 2020

Abstract
Hemojuvelin (HJV) was recently identified as a critical regulator of iron homeostasis. It is either associated with the cells through a GPI-anchor or released as a soluble form. The cellular form acts as a co-receptor for bone morphogenic proteins (BMPs) and activates the transcription of hepcidin, a hormone that regulates iron efflux from cells. Soluble HJV antagonizes BMP signaling and suppresses hepcidin expression. Secretion of HJV requires binding to the transmembrane receptor neogenin. In this study we examined the trafficking and processing of HJV. Cellular HJV reached the plasma membrane without obtaining complex oligosaccharides, indicating that HJV avoided Golgi processing. Secreted HJV, in contrast, had complex oligosaccharides and could be derived from the pool of HJV at the plasma membrane. Neogenin did not play a role in HJV trafficking to the cell surface but was necessary for secretion of HJV, suggesting that it could be involved in either retrograde trafficking of HJV or in cleavage leading to secretion.
Predictors for the Efficacy of Peripheral Blood Progenitor Cell (PBPC) Collection–Results from 4050 Harvests Performed in a Single Centre
Authors: Hoelig Kristina , Kroschinsky Frank , Kramer Michael , Blechschmidt Matthias , Zimmer Kristin , Oelschlaegel Uta , Rutt Claudia , Bornhaeuser Martin , Ehninger Gerhard 
Published: April 2020

Abstract
Background : Peripheral blood progenitor cells (PBPCs) are routinely applied worldwide for allogeneic related and unrelated stem cell transplantation. Factors influencing the mobilisation of PBPC’s in healthy donors are poorly understood. The database of the Apheresis Centre at the University of Dresden was evaluated to identify predictors of PBPC mobilisation.
Methods : 4050 PBPC collections (3928 first donations, 122 second donations) of healthy unrelated donors between 1/1996 and 1/2008 were carried out according to a standardized protocol and prospectively documented in a database. Peripheral blood CD 34 counts were performed before each leukapheresis. CD 34 yield of every PBPC product was calculated in absolute numbers and per kg body weight of the recipient. All parameters are presented as median and range. Mann-Whitney test was performed for discrete variables. Correlation analysis by Pearson was applied for continuous variables. Multivariate regression analysis was carried out to detect factors independently predicting mobilization efficacy.
Results : The range of peripheral CD 34+ haematopoietic stem cells obtained on day 5 was 8.7–285/μl (median 67.5/μl) in male and 6–282/μl, (median 51/μl) in female donors. The median CD 34 yield from the first leukapheresis was 5.88 ×108. Inadequate CD34-yields (&lt; 2 × 106/kg) were obtained only in 18 donors (0.45%). Peripheral CD 34 count at day 5 is significantly correlated with (positive linear regression): BMI, baseline platelet count, male sex, G-CSF application (split dose), baseline leukocyte count. Peripheral CD 34 count at day 5 correlates negatively with: female sex, single dose G-CSF application, regular alcohol consumption and regular smoking status. Linear regression analyses revealed no significant influence of donor age. Multivariate correlation analysis included sex, BMI, baseline platelets, G-CSF-application, baseline leukocytes, age and smoking. This model explained 21.2 % of the variabilityA strong correlation exists between peripheral CD 34-counts at day 5 and apheresis yield (70% of the variability explained).
Conclusions : A dose of 7.5 μg/kg/d lenograstim proved to be safe and effective in a large cohort of unrelated donors for mobilizing sufficient haematopoietic progenitor cells for allogeneic transplantation. Our analysis of 4050 donations revealed significant, but very weak correlations of the peripheral CD 34-counts with donor characteristics and life style parameters. No single parameter derived from donor baseline investigation reliably predicts CD 34 yield. Further evaluation of healthy donors including comprehensive genomic linkage analysis is necessary to elucidate the variable efficiency of PBPC mobilization
Early Events in the Clonal Evolution in Patients with Chronic Lymphocytic Leukemia Carrying TP53 Mutations and 17p Deletion
Authors: Ghia Emanuela M. , Rassenti Laura , Kipps Thomas J 
Published: April 2020

Abstract
The leukemia cells of patients with chronic lymphocytic leukemia (CLL) may experience clonal evolution of TP53 mutations and/or deletions in the short arm of chromosome 17 (del(17p)). Such changes are associated with poor prognosis and resistance to standard chemotherapy. We evaluated for TP53 mutations and p53 protein expression before and after irradiation in leukemia cells with del(17p) of 14 patients at various times prior to therapy. The proportion of leukemia cells harboring del(17p) ranged from 3% to 99.5%, as assessed by fluorescence in situ hybridization (FISH). Four cases had less than 5% CLL cells with del(17p) at the initial sample date. Ten out of 14 patients had leukemia cells that used unmutated IGHV (71%), and 9 (64%) or 6 (43%) had CLL cells with high-level expression of ZAP-70 or CD38, respectively. The median time from diagnosis to sample collection was 2.6 years and the median follow up was 3.8 years. We found 10 of 14 (71%) had proportions of CLL cells with del(17p) ranging from 3% to 55%, but no detectable TP53 mutations in exons 5 through 8, where cancer-related mutations in TP53 are most common. These cases also had functional TP53, as assessed by leukemia-cell induction of p53 and p53-target genes in response to ionizing radiation. Four cases of 14 (28.6%) had TP53 mutation within one of the exons studied and constitutive p53 protein expression both before and after irradiation. In particular, 2 patients with del(17p) detected in 83.5% and 93% of the CLL cells, had leukemia-cell somatic mutations in exon 7 of TP53 at codon 244 and codon 242, respectively. A third patient with 99.5% of the CLL cells with del(17p) had a mutation in exon 5 codon 174. We identified heterozygosity in exon 5 at codon 179 associated with constitutive expression of dysfunctional p53 protein in a fourth patient in which only 14% of the CLL cells had del(17p). The mutation observed at codon 179 of exon 5 resulted in an amino acid change from histidine to leucine. Collectively, even though located in the DNA-binding domain of p53, none of the mutations identified were common to hot spot p53 mutations identified in other types of cancer. However similar mutations (histidine to arginine or histidine to tyrosine) at codon 179 were observed in 3 CLL cases recently published (Zenz T. et al. prepublished Blood 2008) on samples collected at 0, 5, 9 months from diagnosis, respectively. This study reveals early events in the clonal evolution of CLL leading to loss of p53 function, which can be found even in cases that have less than 20% leukemia cells harboring del(17p), as assessed by FISH. It also suggests that mutations at codon 179 might be a common hot spot in CLL, which potentially could provide for another means with which to evaluate for cases at risk for developing drug-resistant disease either spontaneously or following standard chemotherapy.
The CD4+CD25highregulatory T Cell Reconstitution after Allogenetic Stem Cell Transplantation and Its Correlations with aGVHD
Authors: Li Caixia , Depei Wu , Sun Dao ping , Liu Yuejun , Chang Weirong , Zhu Ming qing , Cen Jiannong , Qiu Qiaocheng 
Published: April 2020

Abstract
Background CD4+CD25+ regulatory T cell (Treg), the most significant subset of regulatory T cells, has been found to play an important role in suppressing allogenetic immune response and controlling GVHD recently. The present single-center study monitored the ratio of CD4+CD25high T cells and the expression of FOXP3 gene in peripheral blood post-transplant to assess the reconstitution of CD4+CD25high Treg early after allogenetic stem cell transplantation and its correlations with aGVHD.
Methods: 22 patients undergoing allo-HSCT were enrolled. To detect the CD4+CD25+T cells and the CD4+CD25high T cells subpopulations ratio in CD4+ T lymphocytes(CD4+CD25+/CD4+ ACD4+CD25high/CD4+) Athe CD4+CD25high T cells subpopulations ratio in CD4+CD25+ T cells(CD4+CD25high/CD4+ CD25+) Aand the expression of FOXP3 mRNA in the donor graft and periperal blood frequently after transplantation with the flow cytometry and real-time PCR assays.
Results: \|[Dagger]\|@CD4 +CD25high/CD4+ and CD4+CD25high/CD4+CD25+ ratios in the donor graft were significantly lower in the aGVHD group(P&lt;0.05)‡AEarly after transplantation, Both groups’CD4+CD25+/CD4+ ratio in peripheral blood increased significantly than that in the donor graft(P&lt;0.05).CD4+CD25high/CD4+ and CD4+CD25high/CD4+CD25+ ratios were also significantly higher than that in donor graft in the aGVHD group, but not in the no-aGVHD group.‡BThe expression of FOXP3 in two groups after transplantation increased gradually, until six months after transplantation, its expression was still below the control level(P&lt;0.05). The expression of FOXP3 was lower in the aGVHD group.
Conclusion: \|[Dagger]\|@The early activation and proliferation of the CD4+CD25high regulatory T cells is critical for the maintainance of immune hemostasis and the control of aGVHD.‡AThe occurrence of aGVHD is related with lower ratios of CD4+CD25high regulatory T cells in CD4+T cells and activated CD4+ effector T cells.‡BaGVHD may affect the quantities of CD4+CD25high regulatory T cells and the expression of FOXP3.
Highlighting TH-1 Rather Than TH-17 Cytokine Network in Acute Cutaneous Gvhd
Authors: Keerthivasan Shilpa , Xin Hong , Qin Jian-Zhong , Miele Lucio , Stiff Patrick , Nickoloff Brian J 
Published: April 2020

Abstract
Graft versus Host disease (GVHD) is a major lethal complication of allogeneic hematopoietic stem cell transplantation (HSCT). As skin is one of the major organs involved and the most accessible, it serves as an ideal organ site to further understand the pathogenesis and progression of acute GVHD and could serve as a window into pathophysiology of other organ sites. Cytokine network aberrations are a central feature of the pathogenesis of acute cutaneous GVHD, terminating in the hallmark of premature apoptosis of keratinocytes. The purpose of this study is to delineate the cytokine network aberrations at the molecular and cellular level in affected skin from patients with acute GVHD with the goal of developing novel therapeutic approaches to defined targets with the goal of preventing or reducing acute GVHD. We performed immuno-phenotypic profiling of acute cutaneous GVHD biopsies determining relative numbers of various types of immunocytes including T cells, dendritic cells, and macrophages. Cytokine expression (IFNγ and TNFα) was determined by RT-PCR on RNA extracted from eight different lesional skin and two non-lesional biopsies. We analyzed for TH-1 (IFN γ and TNFα), TH-2 (IL-4) and TH-17 (IL-17A, IL-22) cytokine mRNAs. We observed that TH-1 cytokine mRNAs were detected in 7 out of 8 different lesional skin biopsies but none of two nonlesional skin biopsies. Interestingly TH-2 and TH-17 cytokine mRNAs were not detectable in acute cutaneous GVHD lesions or nonlesional skin biopsies. RNA extracted from a 2-way mixed lymphocyte reaction (MLR) served as a positive control for these RT-PCR results. Given recent data that suggested that Notch-1 regulated TH-1 polarization by transcriptionally controlling the Tbx gene (MinterLM et al 2005), we hypothesized that inhibiting Notch signaling might be of potential therapeutic importance given these results of TH-1 polarization in acute skin GVHD. To block Notch signaling we utilized several pharmacological gamma secretase inhibitors (which may have therapeutic applications), and supplemented this pan-Notch receptor inhibition approach by use of a Notch-1 specific siRNA. Preliminary studies suggest that both approaches reduce IFN γ levels in allogeneic T cell responses in-vitro. Further experiments are in progress to confirm these findings and to determine the molecular mechanism. This study begins to define the cytokine network operative within acute cutaneous GVHD lesions highlighting the finding that TH-1 rather than TH-17 cytokines may be the more important target.
Serum Levels of Soluble Annexin II in Patients with APL
Authors: Kawasugi Kazuo 
Published: April 2020

Abstract
Acute promyelocytic leukaemia (APL, M3) is associated with both a characteristic t(15;17) and severe bleeding diathesis caused by disseminated intravascular coagulation (DIC) and/or hyperfibrinolysis. It has been suggested that annexin II, a coreceptor for tissue plasminogen activator (t-PA) and plasminogen (PLG), is overexpressed on the surface of promyelocytes, leading to an increased fibrinolytic potential. However, little is known about the serum levels of annexin II in patients with APL. Therefore, we measured concentrations of annexin II in sera from patients with APL (n=10). The serum annexin II levels were determined by following methods (sandwich ELISA).
The EIA plates coated for 48h at 4· with 2ug human annexin II antibodies (monoclonal) in carbonate buffer pH 9.4 respectively. The plates were then washed once with PBS and were done for non-specific blocking with 200ul/well PBS containing 1% BSA (PBSA) for 2h at room temperature (RT). After blocking, the plates were washed once with PBS. Subsequently, 100ul of samples diluted by ten times were added to the wells. After 2h incubation at RT, the plates were washed twice with PBS containing 0.05% Tween20 (PBST) and human annexin II rabbit antibodies (polyclonal) diluted 1:250 with PBSA were added to the wells. After 2h incubation at RT, the plates were washed twice with PBST and then incubated for one hour at RT with 100ul/well HRP-conjugated goat anti-rabbit Ig diluted 1:250 in PBSA. The plates were washed twice with PBST and reaction was developed by adding 100ul/well of substrate solution (0.04% O-phenylenediamine in phosphate/citrate buffer pH 5, with 0.04% H2O2). The reaction was stopped after 10 min by adding 50ul/well 2.5M H2SO4, the absorbance was read at 492nm using a spectrophotometer In the patients with APL, we found significant elevations in serum annexin II levels as compared with normal controls.
In other words, serum levels of annexin II were 0.109 (mean OD values, n=10) from patients with APL.
On the other hand, concentrations of annexin II in sera from normal controls were 0.092 (mean OD values, n=10). There was correlation between the FDP and annexin II levels in the APL patients with DIC The present work demonstrates significant elevations in serum annexin II levels in patients with APL. Therefore, we suggest that elevation of annexin II may be associated with the development of an increased fibrinolytic potential.
Autoimmune Thrombocytopenic Purpura in a Patient with Renal Clear Cell Carcinoma
Authors: Xu Li , Ying Shaoxu , Li Xiao 
Published: April 2020

Abstract
A case of renal clear cell carcinoma associated with autoimmune thrombocytopenic purpura is reported. A 56-year-old man presented as thrombocytopenia (10,000/microl) was diagnosed as idiopathic thrombocytopenic purpura after certain tests. He was started on large dose of steroid, intravenous gamma globulin, TPO and multiple platelet transfusion. Platelet count was not stable. Then computerized tomography revealed a left renal tumor 46×25×31mm3. Based on the diagnosis of left renal neoplasm, left nephrectomy with preoperative high-dose intravenous gamma globulin and platelet transfusion was performed. Pathological examination revealed clear cell carcinoma. After the operation, the platelet count increased gradually. But the tumor metastasized 4 months later. Therefore, we consider that extensive tests shall be run to exclude cancer before confirming diagnosis of ITP, the elder patients, or the patients with poor therapeutic efficacy or cortisone dependent. We do not recommend using Cs as the treatment for Cancer-related ITP-like Syndrome. The tumor should be controlled first as soon as possible. If the cancer is localized, IVIG and platelet transfusion can be an appropriate initial treatment for upgrading platelet counts quickly to win time for surgery.
Characterization and Prevalence of Anemia in Subjects with Spinal Cord Injury
Authors: Santos Filipe Nadir Caparica , Pithon Karla ROCHA , Cliquet Marcelo G , Cliquet Alberto 
Published: April 2020

Abstract
INTRODUCTION: Anemia has been considered to be very prevalent in chronic diseases, commonly due to blood loss or inflammatory reasons; as so, it has been considered common sense to imply that anemia is also frequent among subjects with spinal cord injury. Likewise, malnutrition, reenforced by the common association between depression and spinal cord injury, justify the study of the prevalence of anemia in this population.
OBJECTIVE: To evaluate the prevalence of anemia among subjects with spinal cord injury, and its relation with the injury level and also if there is any difference when comparing patients from the Spinal Cord Injury Rehabilitation Ambulatory of UNICAMP (SCIRAU) and outpatients that weren’t previously followed by us, considered as controls; if anemia is found to be present, we intend to evaluate its etiology.
METHODOLOGY: Patients with spinal cord injury from SCIRAU and controls were randomly selected to be enrolled in this study, being 77,3% male (n=17) and 22,7% female (n=5). These patients were evaluated as of their level of injury (separated into paraplegic vs. tetraplegic) and age, being invited to offer a blood sample for analysis of hematological parameters; hemoglobin (Hb) and hematocrit were evaluated. To be considered as being anemic, the cutoff point was 12,0 g% for females and 13,0 g% for males.
RESULTS: The male group had a median age of 31.9 years, significantly lower then the female group, with a median of 46.4 years [p=0.02]. The median value of hemoglobin in the male group (M=14.72, SD=1.23) was statistically higher than the female group (M=12.78, SD=0.17) [p=0.00001]. Comparing the results of Hb between the paraplegic (M=14.48, SD=1.67, N=10) and tetraplegic (M=14.125, SD=1.10, N=12) patients, there were no statistically significant difference [p=0.56]. Such difference also was not confirmed when comparing SCIRAU patients (M=14.44, SD=1.43, N=18) and outpatients from the control group (M=13.58, SD=0.77, N=4) [p=0.16].
CONCLUSION: Surprisingly, none of the patients involved in this study had anemia. The difference between the hematological parameters when comparing male and female subjects was already expected and should not be attributed to the age difference. No significant relation between the level of injury and hemoglobin level were observed. As such, no difference could be seen among patients followed in our SCIRAU and control outpatients. Hence, even though spinal cord injury is considered to be a chronic disease and scientific literature suggest that these patients are at risk for malnutrition and depression (both associated with a higher prevalence of anemia), the hypothesis that these subjects present with a higher prevalence of anemia could not be seen in our study.