bluuebunny/crossref_metadata_2025_split huggingface dataset:
Increased Midkine Gene Expression in Childhood Acute Leukemia.
Authors: Hidaka Hirokazu , Yagasaki Hiroshi , Takahashi Yoshiyuki , Horibe Keizo , Kadomatsu Kenji , Kojima Seiji 
Published: October 2019

Abstract
Midkine (MK) is a heparin-binding growth factor and overexpressed in a number of solid tumors, contributing to their growth. Its expression in acute leukemia, however, has not been clarified. We examined relative levels of MK gene expression defined in K562 cells as 1.00 using real-time quantitative polymerase chain reaction (PCR) in 94 children with acute leukemia and compared with those in normal bone marrow (BM; n=18) and peripheral blood (PB; n=10). Median age was 6 years (range, 0–15 years). Diagnosis included B-precursor ALL (n=41), T-ALL (n=14), B-ALL (n=4), Ph1-ALL (n=6), infant ALL (n=5) and AML (n=24). 8 normal BM samples were separated into CD34+ and CD34− fractions. MK gene expression was detected in normal control samples. Median MK gene expression level was significantly lower in normal PB (2.9×10e-3) than in normal BM (8.0×10e-3) (p<0.01). Expression of MK gene was higher in normal CD34+ BM cells (0.78×10e-3) than in normal unfractionated BM cells (p<0.001). Overexpression of MK was difined as expression at least twice as high as the maximal MK gene expression in normal PB and BM. In 30 of the 41 patients with B-precursor ALL (73.2%), MK gene is overexpressed. We classified B-cell lineage ALL into 3 stage:
DR+,CD19+,CD10+,CD20−,slg−, DR+,CD19+,CD10+,CD20+,slg−, DR+,CD19+,CD20+,slg+.
MK gene expression decreased with B-cell lineage differentiation of leulkemic blast. It was also overexpressed in more than half of the patients with FAB M1 and M2 types of AML. In contrast, overexpression of MK gene was observed only in one of the 13 patients with T-ALL and none of the 6 patients with AML-M5. Supporting the possible involvement of MK in carcinogenesis, overexpression of MK may be not only merely assoziated with total development but also related to leukemic transformation of hematopoietic progenitors. Quantification of MK gene by real-time PCR is relatively simple and widely applicable in patients with acute leukemia. This technique offers particular promise as a prognostic marker and a marker for minimal residual disease in children with B-precursor ALL.
Aberrantly Expressed Neutrophil Elastase (ELA2) Cleaves Cyclin E (CCNE) in the Nucleus and Cytoplasm of Acute Lymphocytic Leukemia Yielding Novel Leukemia-Associated Antigens.
Authors: Ishiyama Ken , Kondo Yukio , Wieder Eric D. , Lu Sijie , Molldrem Jeffrey J. 
Published: October 2019

Abstract
We have shown that donor-derived cytotoxic T lymphocytes (CTL) are specific for two HLA-A2-restricted peptides derived from CCNE (CCNE1144–152, ILLDWLMEV and CCNE2144–152, ILLDWLLEV) specifically lyse lymphoid and myeloid leukemia cells that aberrantly express CCNE. The CCNE protein is overexpressed in AML, ALL, and CML, and in solid tumors such as breast, lung, and gastric cancers. Furthermore, five low molecular weight forms (LMWFs) of CCNE, which are constitutively active to promote cell division, are found only in malignant cells, though it is not known how LMWFs are formed in leukemia. We hypothesized that the cleavage of CCNE into LMWFs occurs by enzymatic cleavage from aberrantly expressed ELA2 in leukemia, which renders the leukemia susceptible to killing by ELA2- and CCNE-specific CTL. Whole cell lysates from U937, HL60, and bone marrow from patients with B-ALL, but not from PBMC or bone marrow cells from healthy donors or ALL patients in remission, showed high expression of CCNE and LMWF by western blot (WB). Recombinant ELA2 added to B cell-derived whole cell lysates increased LMWFs, and the leukocyte elastase inhibitor Elafin prevented this cleavage. Subcellular fractions studied by coimmunoprecipitation showed that ELA2 was bound to CCNE in the nucleus, cytoplasm, and membrane-bound organelles of B-ALL, but not in normal cells. Because nuclear expression of CCNE increases during normal cell division, we studied healthy donor PBMC stimulated with anti-CD3 and anti-CD28 and found no expression of ELA2 or CCNE LMWFs by WB. We conclude that ELA2, normally expressed only in myeloid cells, is also expressed in some ALL blasts, and this data explains how CCNE LMWFs are formed in leukemia. Our findings also suggest how ELA2-mediated cleavage of the PML-RARα fusion product, required for leukemic transformation, could occur when ELA2 is aberrantly expressed in the nucleus. Finally, this work implies that overexpression of CCNE and the LMWFs that contain the immunogenic peptides could increase susceptibility of leukemia cells to CCNE-CTL lysis.
Selection of Human Anti-CD22 scFvs from an Acute Lymphocytic Leukemia Related scFv Library with Ribosome Display.
Authors: Rothe Achim , Hosse Ralf J. , Nathanielsz Anne , Oberhaeuser Frank , von Strandmann Elke Pogge , Engert Andreas , Hudson Peter J. , Power Barbara E. 
Published: October 2019

Abstract
Novel in vitro methods for screening of antibody libraries against disease-related antigens have led to the development of powerful protein-based biotherapeutics. Ribosome display represents an emerging and innovative in vitro technology for the rapid isolation and evolution of high-affinity peptides or proteins. Eukaryotic ternary ribosome complexes can be used to display human single chain antibodies (scFvs) in order to isolate specific binding reagents. Here we present the isolation of human scFv against the validated immunotherapeutic target antigen CD22 from a leukaemia patient-derived human scFv library using ribosome display technology. The ribosome-displayed scFv were enriched against the human CD22 conjugated to magnetic beads. Isolated constructs were further affinity-matured and specific target recognition was demonstrated by surface plasmon resonance and validated using in vitro cell assays.
Oral Etoposide Is Equivalent to Intravenous Administration within the CHOEP-Regimen - Results of a Comparative Pharmacokinetic Study.
Authors: Kroschinsky Frank P. , Friedrichsen Kai , Mueller Juliane , Haenel Mathias , Ehninger Gerhard , Schleyer Eberhard 
Published: October 2019

Abstract
The addition of etoposide to the CHOP protocol (CHOEP) has been shown to improve outcome particularly in younger patients (<60 years) with aggressive non-Hodgkin’s lymphoma [Pfreundschuh, Blood 2004]. In the previous trials a dose of 100 mg/m2 etoposide was given intravenously on three consecutive days representing a disadvantage of CHOEP compared to standard CHOP in terms of patients’ convenience. Therefore we investigated the pharmacokinetic equivalency of etoposide as an oral preparation on days 2 and 3 compared to the intravenous route. Ten patients (male, n=7; female, n=3; median age 56 years) with aggressive B-cell- (n=9) or T-cell- (n=1) lymphoma were included. The CHOEP regimen consisted of cyclophosphamide 750 mg/m2, doxorubicin 50 mg/m2, vincristine 2 mg/m2 and prednisone 100 mg orally days 1 to 5. Etoposide 100 mg/m2 was given intravenously on day 1, and 200 mg/m2 orally on days 3 and 4, respectively. EDTA blood for pharmacokinetic study were taken on days 1 (i.v. study) and 3 (p.o. study) before etoposide and after administration at 30, 60 and 90 min, every hour until 8 hours, followed by samplings at 16, 20, 24 and 48 hours. The samples were centrifuged immediately at 5°C for 15 min, and the plasma was aliquoted into cryo vials and stored at −20°C until assayed. Etoposide levels in plasma were determined by high-performance liquid chromatography (HPLC). The area under the plasma etoposide concentration versus time curve (AUC), plasma etoposide clearance (CL), volume of distribution in steady state (VDss) and terminal etoposide plasma half-life (t½) for the intravenous and oral administered drug were calculated based on the TOPFIT computer program. The median bioavailability after oral etoposide was 58 % with an interpatient variation (coefficient of variation, CV) of 26 %. AUC was very similar after 200 mg/m2 oral etoposide and intravenous administration of 100 mg/m2 of the drug, however the pharmacokinetic variation was higher after oral uptake compared to the parenteral route (35 % vs. 23 %). Data are presented in detail (medians and ranges) in Table #1. We conclude that, within the CHOEP regimen, the intravenous administration of 100 mg/m2 etoposide on days 2 and 3 can be replaced by 200 mg/m2 of the oral preparation, which simplifies the treatment in the outpatient setting.
Table #1 100 mg/m2 Etoposide i.v. 200 mg/m2 Etoposide p.o. C max [μg/ml] 16.7 (10.1 – 21.1) 13.4 (5.8 – 16.8) V ss [L] 14.4 (10.7 – 18.3) 15.1 (10.6 – 25.4) CL total [ml/min] 45.9 (29.6 – 62.8) 82.5 (45.5 – 151.0) CL renal [ml/min] 17.2 (9.4 – 52.6) 16.3 (4.7 – 39.7) t 1/2 [h] 4.1 (3.8 – 5.4) 5.8 (3.2 – 8.3) AUC [μg × h/ml] 72.5 (44.3 – 93.4) 81.6 (44.0 – 147.0)
Re-Treatment with Rituximab Plus Chemotherapy in Patients with Aggressive Lymphoma Treated Previously with CHOP or CHOP-Like Combinations Plus Rituximab.
Authors: Palacios Andres , Navarrete Mayda , Gallur Laura , Zuazu Javier , Barrenetxea Cristina , Sanchez Eva , Lopez Andres 
Published: October 2019

Abstract
Introduction. CHOP plus Rituximab has become the standard treatment for patients with aggressive B-cell lymphoma - particularly DLBCL -, after having shown a better response rate and event free survival over CHOP. However, a number of patients are resistant or relapse (R/R) after a good response. The aim of this study is to assess the efficacy of different Rituximab-containing regimens as salvage therapy in refractory/relapsed (R/R) patients with aggressive lymphoma who had been treated with R-CHOP or R-CHOP-like regimens as first-line therapy.
Patients and Methods. Thirty-six consecutive patients (34 evaluable for response) from the the same institution were reviewed. Twenty-five patients had diffuse large B-cell lymphoma, 4 mantle-cell lymphoma, and 7 Grade 3b follicular lymphoma. Patients received R-CHOP (n=21), DA-R-EPOCH (n=12) orR-Hyper-CVAD (n=3) as first-line therapy. The following salvage regimens were used in this study: R-ESHAP (n=1), R-ICE (n=10), R-TT (n=4), R-GemOx (n=13), Rituximab monotherapy (n=7), and R-MC (n=1). The first three of these regimens were considered ‘aggressive’ (AG) and the three remaining regimens were considered ‘less aggressive’ (LAG).
Results. Median patient age was 59.6 years (range: 31–84 years). The overall response rate (ORR) was 53% (38% complete response [CR]; 15% partial response {PR]. CR directly correlated with IPI score at relapse or therapy failure. ORR was similar in both types of regimen, however the response quality (determined as % CR) was 45% with the LAG regimen and 22% with the AG regimen.With a median follow-up of 29 months the overall survival (OS) was 53% and the event free survival (EFS) was 22%. EFS correlated inversely with IPI at relapse or therapy failure (P=0.015) and directly with response to salvage therapy (P=0.0002). in addition, EFS was slightly higher in patients treated with LAG regimen (42% vs 20%); however this was not statistically significant.
Conclusion. Some authors have hypothesised that ORR appears to decrease when patients who had previously received Rituximab + chemotherapy for first-line therapy were treated with Rituximab + chemotherapy as salvage therapy at relapse. However, our data indicate that responses to Rituximab + chemotherapy continue to occur in these patients. In addition, ‘aggressive’ salvage regimens do not achieve better responses. Large, prospective studies are requires in order to verify the findings of this study.
Abnormal Polarization of T Lymphocyte in Myelodysplastic Syndrome Marrow and Its Negtative Effect on Hematopoiesis.
Authors: Wu Lingyun , Li Xiao , Chang Chunkang , Ying Shaoxu , Pu Quan 
Published: October 2019

Abstract
Objective: To explore polarization of T lymphocyte and its relationship with apoptosis of marrow cells in patients with myelodysplastic syndromes (MDS).
Methods: Measurement of Th1, Th2, Tc1, Tc2 subsets of marrows from 35 patients with MDS and 13 normal controls was performed by flow cytometry. INF-γ and TNF-α in the bone marrow serum were tested by ELISA (Enzyme-linked immunosorbent assay). Furthermore, apoptosis index of marrow cells was detected by TUNEL (TdT-mediated dUTP nick end labeling). Correlation among Th1, Th2, Tc1, Tc2 subsets and INF-γ, TNF-α level as well as apoptosis index were analyzed, and relationship between TNF-α, INF-γ level and apoptosis index was also investigated.
Results:
The percentage of Th1 cells (10.1±1.5%), Tc1 cells (24.2±3.5%) and Tc1/Tc2 ratio (49.7±10.8) was significantly increased in patients with MDS when compared to normal controls (4.0±0.5%, 5.8±0.6% and 13.4±2.7, respectively). Level of INF-γ (57.4±21.9pg/ml) and TNF-α (14.6±3.7pg/ml) in bone marrow serum of patients with MDS was markedly elevated compared to normal controls (0 and 0.3±0.2pg/ml, respectively). An increased apoptosis index of nucleated cells was also observed in patients with MDS (7.2±1.5%) when compared to controls (2.1±0.3%, P<0.05). The Th1 cells percentage showed a positive correlation with level of INF-γ and TNF-α (r=0.38, P<0.05 and r=0.39, P<0.05, respectively), and also a positive correlation with apoptotic index of nucleated marrow cells in patients with MDS (r=0.33, P<0.05). Furthermore, a positive correlation was observed when the relationship between INF-γ, TNF-α level and apoptotic index of marrow cells were analyzed (r=0.74, P<0.01 and r=0.73, P<0.01, respectively). Th1, Tc1 cells and Tc1/Tc2 ratio in patients with RCMD (according to WHO classification) was markedly elevated (P<0.01) while not significantly increased in patients with RCMD-RS, RAEB-1 and RAEB-2 when compared to normal controls. An elevation in the percentage of Th1 (11.1±1.9%), Tc1 (25.1±3.8%) and Tc1/Tc2 ratio (58.6±15.8%) was detected in patients with lower-risk (defined by IPSS), while there was no difference between higher-risk group and controls.
Conclusions: Th1/Th2, Tc1/Tc2 in bone marrow of patients with MDS were unbalanced, which were polarized to typeIreaction especially in patients with RCMD subtype and lower-risk group. The increased Th1 cells in marrow may account for apoptosis of nucleated marrow cells in MDS, which may act through proapoptotic cytokines such as INF-γ and TNF-α.
Comparative Pharmacokinetic/Pharmacodynamic Profiles in Japanese and Caucasian Patients with Transfusional Hemosiderosis Receiving Treatment with Deferasirox (Exjade®, ICL670).
Authors: Iki S. , Urabe A. , Hata T. , Ohyashiki K. , Nakao S. , Takatoku M. , Ishikawa T. , Kato J. , Tatsumi Y. , Mori H. , Tanii H. , Taniguchi J. , Kondo M. , Schran H. , Rabault B. 
Published: October 2019

Abstract
Introduction: In Japan, myelodysplastic syndromes (MDS) and aplastic anemia (AA) are the most common transfusion-dependent anemias. Deferasirox (Exjade®, ICL670) is a once-daily, oral iron chelator for the treatment of transfusional iron overload; its efficacy and tolerability have been established in adults and children with a range of transfusion-dependent anemias, including MDS. Here, deferasirox has been evaluated in Japanese patients and the pharmacokinetics (PK) and pharmacodynamics (PD) compared with those seen in a US study.
Methods: The tolerability, PK and PD of deferasirox have been assessed in a Phase I, open-label, unblinded, dose-escalation trial (1101) in Japanese patients with MDS and AA in 9 centers. Deferasirox was administered as a single dose of 5 (n=6), 10 (n=7), 20 (n=6) or 30 mg/kg (n=7). After a 7-day break, daily doses were administered (same doses/same patients) for 7 consecutive days. Data were compared with a study (0104) in 24 Caucasian β-thalassemia patients (age range 18–39 years) who were administered doses of deferasirox of 10, 20 or 40 mg/kg/day for 12 days. Throughout the study, iron intake and excretion were rigorously measured.
Results: A total of 26 Japanese patients (8 male, 18 female; mean age 65.6 years; 8 aged <65 years) completed single- and multiple-dosing periods (16 MDS; 6 AA; 4 other anemias). After a single dose and also at steady state, linear PK (Cmax and AUC) were observed at all doses. The figures show Cmax and AUC at steady state for both the Japanese patients (closed circles, solid lines) and the Caucasian patients (open squares, dotted lines), and demonstrate that PK were similar.
Figure Figure
Dose-dependent iron excretion (range 0.07–0.61 mg iron/kg/day) was observed, similar to that in the Caucasian patients (range 0.12–0.45 mg iron/kg/day). A linear relationship (PK/PD) was noted between AUC and iron excretion. Deferasirox was well tolerated, with generally infrequent and mild adverse events (AEs). The most common AEs related to deferasirox were diarrhea (n=2 each after single and multiple doses of 30 mg/kg/day) and nausea (n=1 each after multiple doses at 10 and 30 mg/kg/day). One patient had two serious AEs, pyrexia and duodenal ulcer, both suspected to be related to study drug, after multiple doses of 30 mg/kg/day.
Conclusions: Deferasirox is well tolerated both after single and multiple doses in Japanese MDS/AA patients, with similar PK/PD parameters to those in the Caucasian β-thalassemia cohort. Exposure to deferasirox in the Japanese patient cohort was dose dependent with a linear PK/PD relationship resulting in dose-dependent iron excretion. These data suggest that deferasirox is effective and well tolerated regardless of underlying disease, race or age.
Retrospective Analysis of Causes and Consequence of Delay in Diagnosis of Multiple Myeloma.
Authors: Kariyawasan Chitranga C. , Hughes Derralynn , Mehta Atul B. 
Published: October 2019

Abstract
We have conducted a retrospective study of 82 patients (49 - male, 33 - female, median age 67 years (Male), 63 years (Female) ) of whom 72 were de novo and 10 had a previous diagnosis of MGUS/Smouldering myeloma/Plasmacytoma. The duration of symptoms prior to diagnosis was used to categorise patients into 4 groups [A - 0 - 3months, B - 3 -6 months, C - 6 - 12 months, D > 12 months]. The incidence of complications of myeloma (infection, renal failure, bone disease, neurological disease and anaemia) were assessed in each group. 25 of 72 patients (35%) were in group A, 47 (65%) were in group B,C and D and 30 of these (64%) had presented initially to a general practitioner. The commonest presenting symptom was bone pain (60%) and skeletal disease was the commonest complication seeing in 43% of group A but in 57% of groups B,C and D. All 18 patients in group D had > 1 complication (median 2, range 1–4) while 9 of 25 patients (35%) in group A had no complication. Four of 25 (16%) patients in group A were in remission or first phase of treatment and 7 of 25 (28%) had survived 5 years or more. In contrast, 9 of 18 (50%) patients in group D had relapsed disease and only 2 had survived 5 years or more. Our findings indicate that a delay in diagnosing multiple myeloma has a significant impact on the course of the disease.
Pre-Clinical Trial on the Co-Transplantation of MSCs and Umbilical Cord Blood Stem Cells.
Authors: Shao-liang Huang , Ke Huang , Dun-hua Zhou , Jian-pei Fang , Yang Li , Chun Chen , Xiang Peng 
Published: October 2019

Abstract
Objective Cotransplantion of Mesenchymal stem cells(MSCs)with UCB-HSC promote the engraftment, accelerate the recovery of hematopoiesis and alleviate the severity of graft versus host disease(GVHD). Cases and methods 18 cases were treated with UD-UCBT (15 cases) and RD-UCBT (3 cases) .of them, acute lymphoblastic leukemia (high risk) 2 cases, acute myeloblastic leukemia 4 cases, chronic myeloblastic leukemia 3 cases, β-thalassemia major 8 cases and, mucopolysaccharidosis 1 case. HLA matched (6/6) in 3 cases, one locus (5/6) were dismatched in 12 cases and two HLA loci (4/6) in 3 cases. UCB was transfused into recipients according to the regular method. The MSCs were from auto-BM in 3 cases, from allogenic bone marrow of parents 4 cases, from allogenic related bone marrow 10 cases, and cord blood MSCs 1 case. The MSCs were transfused by IV (14 cases) or IBM (4 cases) injection. The conditioning regimens modified on the basis of Bu/CY + Fluda + ATG. GVHD was prevented according to the regular method in our department. Infused NCs dose of UCB was 6.77×107/kg, CD34+ÆÞsG5.58×105/kg; allo-MSCs 4.03×106/kg, auto-MSCs 8.83×106/kg. MSCs origin were detected.
Results
Ten cases were full donor engrafted, the time to get ANC ≥0.5×109/L and PLT ≥2.0×1010/L were on the 13.9th day and the 30.8th day. CFU-MIX, MSCs of recipients in Co-transplantation groups recovered gradually from 14th day to 28th day. MSCs origin were detected in 4 cases, all were recipients.
Conclusion
MSCs co-transplantation accelerated HSCs engraftment and hematopoiesis recovery, the time to get ANC ≥0.5×109/L and PLT ≥2.0×1010/L were faster than those of single CBT and UD-BMT. MSCs co-transplantation cannot promote engraftment in CBT of β-thalassemia major. Co-transplantation of MSCs accelerated reconstitution of hematopoietic cells and MSCs.
Vaccination of Leukemia Patients with Autologous In Vitro Cultured Leukemia Dendritic Cells.
Authors: Yue Lu , Geng Qi-Rong , Xia Jian-Chuan , Fan Hui-jie , Xu Hai- , Chen PengXiao-qing 
Published: October 2019

Abstract
OBJECTIVE:To investigate the safety and immunomodulation effect of dendritic cells(DCs)vaccine to leukemia patients cultured in vitro from autologous leukemia cells.
METHOD:Leukemic-dendritic cells were cultured from autologous bone marrow leukemia cells in vitro using combined cytokines. Patients received four administrations of autologous in vitro cultured leukemia-DCs by intravenous injection during chemotherapy intervals when obtain complete remission (CR), once a week for four times. Peripheral blood were collected to analyze the serum Th1/Th2 cytokines as IL-2, IL-4, IL-6, IL-10, IFN-γ, TNF-α by cytokine bead array(CBA) analysis and T cell subpopulations by flow cytometric method (FCM).
RESULTS:A total of 31 patients who are hematologically confirmed as leukemia received the DC vaccination therapy from December 2002 to October 2005. 20 patients can be evaluated. Firstly, autologous leukemic-dendritic cells were cultured in vitro successfully. Secondly vaccinations were well tolerated. No major toxicity occurred in any of the patients. Thirdly, serum cytokines were all elevated 24hs after the first administration of DC vaccination compared to those before that. And IL-2, IFN-γ, IL-4 and IL-6 have statistically significant increases with Z values −2.576, −2.033, −2.777, −2.053 and p values 0.010,0.042,0.005,0.040, respectively. Relative increase of the cytokine levels induced by DC vaccination show a trend of TH1 cytokines advantage, suggesting an enhancing of cellular immune response. T cell subsets significantly increase in CD4/CD8 ratio and CD56 proportion with Z values −2.040, −1.988 and P values 0.041, 0.043, respectively.
CONCLUSIONS:Autologous leukemic-DCs could be generated in vitro from leukemia cells. And the intravenous injection of autologous L-DC vaccine is safe and feasible, and it could enhance the immune response in vivo to a certain degree.