bluuebunny/crossref_metadata_2025_split huggingface dataset:
Early Harvest Followed by Melphalan-Dexamethasone and Second-Line Autologous Stem Cell Transplantation in AL Amyloidosis.
Authors: Palladini Giovanni , Perfetti Vittorio , Russo Paola , Lavatelli Francesca , Nuvolone Mario , Obici Laura , Merlini Giampaolo 
Published: October 2019

Abstract
Autologous stem cell transplantation (ASCT) is considered the most effective therapy in AL, but treatment related mortality (TRM) is significant. Melphalan-dexamethasone (MDex) is well tolerated and grants a high response rate (Blood2004; 103: 2936-8). In order to reduce TRM, after stem cell harvest, we treated AL patients eligible for ASCT with first-line MDex, offering second-line ASCT to non-responders (NR). Eligibility to ASCT was determined according to Comenzo and Gertz (Blood2002; 99: 4276-82), including good and intermediate risk patients. Response to MDex was evaluated every 3 cycles. MDex was continued until either complete remission (CR) or partial hematologic response (PR) associated with organ response (PR+OR) was reached. MDex was discontinued after 3 cycles in NR or after 9 cycles in patients in PR without organ response (PRNOR). Patients in PRNOR or NR received second-line therapy: ASCT if they were still eligible, or thalidomide-dexamethasone (TDex, Blood2002; 105: 2949-51) if they became ineligible for ASCT. Forty patients (median age 55 years, range 32–67 years, 20 males, 15 good-risk) were enrolled between March 2002 and June 2005. Twenty-five (63%) responded to MDex (11 CR, 14 PR). Hematologic response was accompanied by OR in 23 cases. There was no TRM. Seventeen patients (42%), 15 NR and 2 in PRNOR received second-line therapy. Seven were still eligible for ASCT. Although 2 of them were enrolled as good-risk, at the time of ASCT all were intermediate-risk and received conditioning with melphalan 140 mg/m2. Two patients died within 100 days and 2 (29%) responded. The 2 responders had obtained PRNOR after MDex. Ten patients received second-line TDex. One died within 100 days and none responded. Overall, 6 patients (15%), none of whom responded to MDex, died. Median follow-up of living patients is 27 months. Median survival was not reached. Response to MDex improved survival (p<.001). The efficacy and tolerability of MDex is confirmed. Approximately 60% of NR to MDex lose eligibility for ASCT. After MDex, second-line ASCT is associated with apparently increased TRM. Response to second-line ASCT was observed only in patients who obtained PR with MDex.
Results of Autotransplantation in Follicular Large-Cell Lymphoma.
Authors: Copelan Edward A. , Crilley Pamela Ann , Pohlman Brad , Elder Patrick , Pant Shubham , Marathe Pallavi , Brodsky Isadore , Lin Thomas S. , Bolwell Brian J. 
Published: October 2019

Abstract
The role of autotransplantation in the treatment of large-cell follicular lymphoma is uncertain. We analyzed results of autotransplantation performed from 1/91 through 7/06 in follicular large-cell non-Hodgkin’s lymphoma (NHL) at 3 institutions using preparation with busulfan, cyclophosphamide and VP-16 and compared results to those of patients with diffuse large-cell NHL (DLCL) receiving identical preparation over the same period. Fifty-nine patients with follicular large-cell NHL (FLCL) were compared to 430 patients with DLCL. There were no significant differences between the 2 groups in regards to age (DLCL: median 51 years; range 18–74 years; follicular: median 55 years; range 33–77years), sex, remission status at transplantation, bulky disease at diagnosis, or follow-up(median 4 years). Bone marrow involvement at diagnosis occurred more frequently in FLCL patients (P=0.03). Regimen-related mortality at 100 days for patients with FLCL is 4% (95% CI: 0-14%); estimated relapse-free survival at 4 years is 53% (95% CI: 20-83%) and relapse rate at 4 years is 43% (95% CI: 13%-73%). Relapses beyond 4 years occurred in 2 patients with FLCL and 4 with DLCL. Relapse-free survival was adversely affected in both groups by chemotherapy resistant disease or transplantation beyond second remission (P=0.02). There were no significant differences between the two groups in the incidence of early mortality, 4 year lymphoma-free survival, relapse rate at 4 years, or relapse beyond 4 years. In conclusion, the results of autotransplantation in FLCL are similar to those in DLCL. Patients who undergo transplantation in chemosensitive first relapse or earlier have favorable outcomes. Late relapse occurs infrequently.
Lentiviral MDR1 Gene Transfer Confers Radioprotection to Human CD34(+) Haematopoietic Progenitor Cells.
Authors: Maier Patrick , Herskind Carsten , Katharina Fleckenstein , Laufs Stephanie , Zeller Jens W. , Wenz Frederik , Fruehauf Stefan 
Published: October 2019

Abstract
Normal haematopoietic stem cells are particularly sensitive to radiation-induced apoptosis. Overexpression of the multidrug resistance 1 (MDR1) gene product, P-glycoprotein (P-gp), leads to suppression of apoptosis and is radioprotective in the human lymphoblastoid cell line TK6. Therefore, gene therapy with MDR1 might protect bone marrow cells during tumour-radiotherapy. The aim of this study was to test if human CD34(+) blood stem cells can be protected from the effect of radiation by MDR1 gene transduction. MDR1 cDNA was cloned into the lentiviral SIN-vector pHR’SINcPPT-SEW to replace the eGFP cDNA. CD34(+) cells isolated from four individual donors were exposed to lentiviral supernatants with an MOI of 10 of either HR’SIN-MDR1 or HR’SINcPPT-SEW as a control. After lentiviral transduction, 0.8×105 cells of transduced and non-transduced CD34(+) control cells, respectively, were irradiated with 0–8 Gy and held in liquid culture under differentiation conditions. Ten days after irradiation, the amount of MDR1 expressing cells was determined by the Rhodamine-(Rh−)123 efflux assay and the MDR1-expression rate was monitored by real-time PCR. Additionally, the differentiation status was tested with FACS-analyses for CD11b (myeloid and natural killer cells), CD15 (neutrophils, eosinophils, monocytes), CD33 (myeloid progenitor cells, monocytes), and CD34 (hematopoietic precursors) expression. To test the potential of MDR1 to protect differentiated cells, unirradiated cells were irradiated after 10 days in liquid culture. Apoptotic cells were detected 48 hours later by staining with Annexin V. The transduction efficiency for the MDR1-virus was 3–18%, for the GFP-virus 12–60%. The proportion of RH-123-negative (=MDR1-positive) cells of all four donors increased with escalating radiation doses (e.g. 18–54% from 0–8 Gy). Irradiation of the differentiated cells after ten days of liquid culture also led to an increase of RH-123-negative cells with escalating radiation doses (e.g. 12.5–17% from 0–8 Gy). We found a correlation between radiation dose and differentiation status: independent on transduction the amount of CD11b-cells increased at 2–4 Gy (e.g from 23–45%) and decreased to 9% with 8 Gy; a similar course was also seen for CD15 expression. Our results clearly indicate the radioprotective effect of human blood stem cells by lentiviral MDR1-overexpression. Thus, enhancing repopulation by surviving stem cells may increase the irradiation tolerance of hematopoietic cells and thus contribute to widening the therapeutic range in radiotherapy.
Economics of Intravenous Fludarabine Phosphate and Oral Fludarabine Phosphate for the Treatment of B-Cell Chronic Lymphocytic Leukemia in a Developing Country - Brazil.
Authors: Bigni Ricardo , Araújo Gabriela T.B. , Fonseca Marcelo C.M. , Dubin Jane , Coelho Arthur M. , Bello Reinaldo Dal 
Published: October 2019

Abstract
B-cell chronic lymphocytic leukemia (B-CLL) is the commonest leukemia occurring in Western countries, and arises predominantly in older age groups. Intravenous fludarabine phosphate offers the possibility of a prolonged progression-free interval, an increased response rate and a trend toward better tolerability in comparison with standard polychemotherapy regimens. A more convenient oral formulation of fludarabine phosphate, has been developed. We undertook a literature review that has demonstrated that oral fludarabine phosphate has a similar clinical efficacy and safety profile to the IV formulation and does not adversely affect quality of life. Also we performed a retrospective analysis of patients receiving IV fludarabine for (B-CLL) at our institution to determine the management and resource use of these patients. A cost minimization analysis was then conducted. The per patient costs for the treatment of drug-related adverse events were in local currence R$ 1.476,87 for oral fludarabine and R$ 2.119,64 for IV fludarabine. When costs of a full course of each treatment were compared, the costs per patient for oral fludarabine and IV fludarabine were R$ 22.152,43 and R$ 23.160,31 respectively. In this preliminary analysis, considering that oral fludarabine has a similar efficacy rate and tolerability profile to IV fludarabine, the oral formulation appeared to have a lower total cost per patient. These data require confirmation with formal assessment of cost-effectiveness.
Cost Effectiveness of Post-Remission Intensive Therapy in Patients with Acute Leukemia.
Authors: Hsu Hui-Chi , Gau Jyh-Pyng , Chern Hsiouh-Hsiang , Chau Wing-Keung , Tzeng Cheng-Hwai , Ho Chao-Hung 
Published: October 2019

Abstract
Background: We assessed the cost-effectiveness of high dose arabinoside (HiDAC)-based and allogeneic stem cell transplantation (alloSCT)-based therapy in patients with acute leukemia.
Patients and Methods: We analyzed the outcome, cost and cost-effectiveness of 106 patients treated between 01/94 and 01/02 (94 AML/12 ALL). Forty-two young patients at either intermediate or unknown cytogenetic risk received post-remission intensive therapy (24 HiDAC-based / 18 alloSCT-based therapy).
Results: After a median follow-up of 50 months, the estimated 7 year overall survival for the HiDAC-based group showed a tendency to be higher than the alloSCT-based group (48% versus 28%; p=0.1452). HiDAC-base group spent a significantly lower total cost (USD 51,857 versus 75,474; p=0.004) than the alloSCT-based group. Cost-effectiveness analysis showed that the mean cost per year of life saved for the HiDAC-based group is considerably less expensive than the alloSCT-based group (USD 11,224 versus 21,564). The reduced total cost for the HiDAC-based group originated from lower cost in room fees, medication, laboratory and procedure, but not in blood transfusion and professional man-power fees.
Conclusion: HiDAC therapy as initial post-remission intensive therapy is a cost-effective approach in AML patients at either intermediate or unknown cytogenetic risk, which deserves further prospective clinical study to address this issue.
Trisomy 21 Expands the Megakaryocyte-Erythroid Progenitor Compartment in Human Fetal Liver-Implications for Down Syndrome AMKL.
Authors: Tunstall-Pedoe Oliver , de la Fuente Josu , Bennett Phillip R. , Fisk Nicholas M. , Vyas Paresh , Roberts Irene A.G. 
Published: October 2019

Abstract
Children with Down syndrome (DS) have a uniquely high frequency of acute megakaryoblastic leukemia (AMKL)- ~500-fold increased compared to children without trisomy 21 (T21). At least two genetic events are required but are not sufficient for DS-AMKL: T21 and N-terminal truncating mutations in the key megakaryocytic transcription factor GATA1. This tight association of T21 with GATA1 mutations and the development of AMKL in a narrow temporal window (fetal life-5yrs) makes DS-AMKL a highly informative model of multi-hit leukemogenesis in which the first steps occur in utero. However, the individual contributions of T21 and mutant GATA1 in the leukemogenesis are unclear. To specifically investigate the role of T21 in DS-AMKL and why leukemia-initiation is confined to fetal (or early post-natal) life we have studied fetal hemopoiesis in DS during the second and third trimester in 16 fetuses (gestational age 15–37 weeks) where an antenatal diagnosis of DS with T21 was made by amniotic fluid fetal cell karyotyping. Samples of fetal blood (n=13), fetal liver (n=9) and fetal bone marrow (n=8) were screened for mutations in the GATA1 gene genomic DNA by DHPLC or direct sequencing (sensitivity of detecting a GATA1 mutation is 1–5% by DHPLC). No GATA1 mutations were detected. This allowed us to study the impact of T21 independent of GATA1 mutation on fetal hemopoiesis. DS fetuses showed marked qualitative and quantitative abnormalities in hemopoiesis. While the total number of CD34+ cells in DS and normal fetal liver were comparable, DS fetuses had a striking increase in bi-potential megakaryocyte-erythroid progenitors (MEP; CD34+CD38+FcgloCD45RA+− 74.4% vs 27.0% of fetal liver CD34+/CD38+ cells. Peripheral blood from all DS fetuses studied compared to normal fetal blood samples showed dysmegakaryopoiesis (abnormally shaped and/or giant platelets and MK fragments), dyserythropoiesis (macrocytes, poikilocytes, basophilic stippling), increased numbers of blast cells and also had an increased percentage of MEPs − 40.3% vs 26.9%. By contrast, there was no difference in the number of MEP nor erythroid or MK lineage morphology in DS fetal bone marrow compared to normal fetal bone marrow. CD34+ cells from DS fetal liver and fetal blood expressed both fl GATA1 and GATA1s mRNA indicating that dysmegakaryopoiesis and erythropoiesis were not due to lack of expression of fl GATA1. These data indicate, for the first time, that T21 by itself profoundly disturbs megakaryopoiesis and erythropoiesis and leads to an increased of frequency of MEP. This has important implications since it provides a testable hypothesis for the role of T21 in the initiating step of AMKL, namely that T21 expands a fetal liver-derived progenitor compartment which forms a substrate upon which GATA1 mutations then confer a further selective advantage.
Insufficient Inhibition by Aspirin of Platelet TXA2 Synthesis and Platelet Recruitment Is Associated with Myonecrosis in Patients with ST-Segment Elevation Myocardial Infarction.
Authors: Santos Maria-Teresa , Fuset Maria P. , Moscardo Antonio , Ruano Miguel , Perez Francisca , Breña Silvia , Piñon Marta , Valles Juana 
Published: October 2019

Abstract
Heterogeneity in response to aspirin (ASA) treatment or “aspirin resistance” could be of importance in patients with ST-segment elevation myocardial infarction (STEMI). Reduced effect of ASA in platelets could be due to partial inhibition of cyclooxygenase-1 (COX-1) or to COX-1-independent mechanisms. We evaluated the effect of ASA treatment in patients with STEMI for: a) platelet TXA2 synthesis; b) platelet recruitment elicited by TXA2-dependent and -independent mechanisms and c) the possible association of these aspects of platelet reactivity with serum markers of myonecrosis. We studied 62 consecutive ASA-treated patients shortly after the onset of the acute event. Analytical determinations were performed within 48 h of the onset of the acute event (mean ± SD, 23.12 ± 11.61 h). Fifty-two of the patients were treated with fibrin-specific fibrinolytic agents and 56 were also anticoagulated with enoxaparin. A group of 62 ASA-free and 10 ASA-treated controls were also evaluated. TXA2 synthesis and platelet recruitment (fluid-phase pro-aggregatory activity of cell-free releasates) were assessed after collagen stimulation (1 μg/mL) of whole blood in patients and control subjects. Optimal inhibition of TXA2 and platelet recruitment was assumed if these were greater than 95% and 80%, respectively, compared with the ASA-free population of normal donors. Comparisons between categorical data were performed using chi-squared tests. The Kruskal-Wallis non-parametric test was used for comparisons between groups. A two-sided P value < 0.05 was considered significant. Partial inhibition of TXA2 by ASA was found in 21 patients (34%). This was associated with significant elevations of Troponin-T, CK-MB mass, CK and recruiting activity vs. 41(66%) patients with blocked TXA2 production. This was independent of fibrinolysis and platelet COX-2 expression was not augmented. TXA2 blockade was achieved after subsequent daily treatments or platelet incubation with ASA in vitro, suggesting reduced sensitivity of COX-1 to ASA. In addition, 28 patients (45%) had an abnormally elevated recruiting activity, despite TXA2 blockade, which was also associated with increased myonecrosis. In conclusion, aspirin resistance, elicited by both TXA2-dependent and TXA2-independent mechanisms, was prevalent in patients with STEMI. This study describes for the first time the association of partial platelet TXA2 inhibition with myonecrosis.
Identification and Partial Characterization of Fanconi Anemia Associated Polypeptides (FAAPs) Using a Versatile Multiprotein-Complex Purification Method.
Authors: Ali Abdullah M. , Singh Thiyam R. , Meetei Ruhikanta A. 
Published: October 2019

Abstract
Fanconi Anemia (FA) is an autosomal recessive and X-linked disorder characterized by congenital abnormalities, progressive bone marrow failure, and a high incidence of hematological (acute leukemia) and non-hematological malignancies (squamous cell carcinomas of the head and neck or gynecologic system). FA is genetically heterogeneous disease and to date 12 complementation groups are known of which 11 gene products have been identified (FANC- A, B, C, D1, D2, E, F, G, J, L, M). Eight of the FA gene products, FANCA, FANCB, FANC, FANCE, FANCF, FANCG, FANCL and FANCM form a multiprotein FA core complex. This complex is required for the monoubiquitination of FANCD2 upon DNA damage by various genotoxic agents. The other two FA proteins; FANCD1/BRCA2 and FANCJ are believed to act “downstream” of FANCD2. In order to understand the role of FA proteins in DNA repair pathway it is necessary to find all the FA genes and their interacting partners. We have established a two-step purification method using 6XHis and FLAG tags for the biochemical and functional characterization of the FA core complex proteins. In an attempt to isolate interacting partners of FANCM and FANCL proteins; we have established two different HeLa cell lines; HeLa-HF-FANCM and HeLa-HF-FANCL, stably expressing HF-FANCM and HF-FANCL recombinant proteins respectively. Two step affinity purification was carried out to isolate the complexes from the extracts prepared from stable cell lines. Two polypeptides, namely, FAAP16 and FAAP100 were identified by mass-spectrometry as major interacting partners of FANCM and FANCL respectively. The interaction of FAAP16 and FAAP100 with other FA core complex proteins was confirmed by reciprocal affinity purification coupled mass-spectrometry using HeLa cells stably expressing HF-FAAP16 and HF-FAAP100 proteins. Furthermore, suppression of FAAP16 and FAAP100 in HeLa cells using siRNA resulted in a reduced MMC-induced FANCD2 monoubiquitination. Studies are being carried out to understand the precise role of these proteins in the FA core complex. These data suggest additional proteins interact with FA core complex members and demonstrate the utility of the purification method in delineating interacting proteins involved in FA.
Proteasome Inhibitor/Imatinib Combinations Exert Potentiated Antileukemia Efficacy but Not Cardiotoxicity in Chronic Myeloid Leukemia.
Authors: Zhou Guangbiao , Hu Zheng , Pan Xiaofen , Liu Jinglei , Ma Liyuan , Liu Xiaoli , Meng Fanyi , Li Juan , Chen Zhu , Chen Saijuan 
Published: October 2019

Abstract
Whether imatinib mesylate (IM)-based combinatory regimens could be an option for overcoming limitations of IM in treating chronic myeloid leukemia (CML), e.g., resistance developed by leukemic cells, unsatisfactory efficacy on patients at accelerated and blastic phases, and potential cardiotoxity, warrants further investigation. Here we report that the proteasome inhibitors, Bortezomib (BOR) and PSI, significantly potentiate proliferation/growth inhibition and enhance apoptotic effects of IM on K562 cells, CD34+ cells from CML patients, and BCR-ABL-expressing murine hematopoietic progenitor cells. BOR and PSI potentiate IM-triggered activation of caspases and inactivation of BCR-ABL oncoprotein, while caspase inhibitor blocks the apoptotic effect and reverse BCR-ABL inactivation. BOR/IM and PSI/IM combinations also attenuate DNA binding activity of NFκB. Intriguingly, low dose BOR/IM combination yields potent effects on inhibition of tumor growth, induction of apoptosis in leukemic cells, and inactivation of BCR-ABL oncoprotein, and does not cause weight loss or cardiotoxicity in null mice injected with K562 cells as compared to animals treated with IM at high doses. These results suggest a clinical trial to test the efficacy of IM/BOR combination in treating CML.
Methylprednisolone-Treatment Induces Dephosphorylation of Syk in B-CLL Cells In Vitro.
Authors: Boelens Jerina , Lust Sofie , Van Gele Mireille , Derycke Lara , Janssens Ann , Van Hoecke Barbara , Philippé Jan , Bracke Marc , Poelman Martine , Offner Fritz 
Published: October 2019

Abstract
Glucocorticoids (GCs) are often implemented in the treatment regimens of B-cell Chronic Lymphocytic Leukemia (B-CLL). Apart from caspase-involvement and downregulation of Lyn, the exact mechanisms of action in apoptosis induction in B-CLL remain uncertain. We studied methylprednisolone (MP)-induced apoptosis in B-CLL and found a greater sensitivity of ZAP−70+ B-CLL cells for MP-induced cell death, which was accompanied by a glucocorticoid receptor-dependent decrease of ZAP-70 expression. Micro-array data correlated this downregulation of ZAP-70 with an upregulation of the phosphatase PTP1B (Protein Tyrosine Phosphatase 1B). This observation was confirmed on genomic and protein level by RT-qPCR and Western blotting. Next, functional assays with the phosphatase-inhibitor ortho sodium vanadate and with the PTP1B-inhibitor 3-(3,5-Dibromo-4-hydroxy-benzoyl)-2-ethyl-benzofuran-6-sulfonicacid-(−4-(thiazol-2-ylsulfamyl)-phenyl)-amide were performed. Both drugs were able to inhibit the GC-induced ZAP-70 downregulation, which is suggestive for the role of PTP1B. In order to explore this further, we studied the effect of MP on the phosphorylation of Syk by Western blotting and flow cytometry. We did not take phosphorylated ZAP-70 into account as phosphorylation of ZAP-70 is very unclear in CLL cells. We observed GC-induced dephosphorylation of Syk (tyrosine residues 352 and 526), associated with a decrease of total Syk. The kinetics were completely in accordance with those of the ZAP-70 downregulation, occurring only after 12 hours after the start of treatment. Next, we performed immunoprecipitation experiments to investigate the reciprocal influence of Syk and ZAP-70 and found co-immunoprecipitation of Syk, ZAP-70 and hsp90, suggesting a close relation of ZAP-70 and Syk in performing their tasks. In spite of the unclear status of ZAP-70 phosphorylation, ZAP-70 positive B-CLL cells allow for more effective IgM-signaling than their ZAP-70 negative counterparts, probably by blocking inhibitors of signalling through Syk. Moreover, ZAP-70 positive B-CLL cells undergo stronger and prolonged BCR-induced phosphorylation of tyrosine residues 352 and 526 of Syk, which are already prominent in unstimulated conditions. The kinetics and concentration overlapping downregulation of ZAP-70 and dephosphorylation of Syk after MP treatment suggests a relation between these two protein tyrosine kinases in performing their tasks. This was further strengthened by the observation of a co-immunoprecipitation of ZAP-70, Syk and hsp90. In conclusion, in vitro GC treatment of ZAP-70+ B-CLL cells is associated with a downregulation of ZAP-70 and a dephosphorylation of Syk tyrosines 352 and 526 via a GR-dependent way. The upregulation of PTP1B at both genomic and protein level, and the results of the functional assays, are suggestive for a role of this phosphatase during treatment with GCs.