bluuebunny/crossref_metadata_2025_split huggingface dataset:
Acute Myeloid Leukemia Cells Are Resistant to Tumor Necrosis Factor-Related Apoptosis-Inducing Ligand (Apo2L/TRAIL) by a Mechanism Independent of Multidrug Resistance.
Authors: Fricke Stacy M. , Minderman Hans , O’Loughlin Kieran L. , Cheng Jinrong , Repasky Elizabeth A. , Baer Maria R. 
Published: April 2020

Abstract
Multidrug resistance (MDR) associated with overexpression of the ATP-binding cassette (ABC) proteins P-glycoprotein (Pgp), multidrug resistance protein (MRP-1) and breast cancer resistance protein (BCRP) is an obstacle to the successful treatment of AML. Apo2L/TRAIL binds to the extracellular death receptors DR4 and DR5 and induces tumor-specific apoptosis in diverse malignancies. Given that Apo2L/TRAIL induces apoptosis via signal transduction pathways, it has the potential to be effective in cells with MDR mediated by ABC proteins. Cell lines with MDR mediated by ABC proteins and acute myeloid leukemia (AML) cells from 10 patients (6 untreated, 4 relapsed/refractory) were tested for expression of the Apo2L/TRAIL receptors DR4 and DR5 and decoy receptors DcR1 and DcR2 by flow cytometry and for cytotoxic and pro-apoptotic effects of Apo2L/TRAIL (Genentech, Inc.). Parental HL60 and 8226 cells and resistant HL60/VCR (Pgp) and HL60/Adr (MRP-1) cells demonstrated expression of DR4 and DR5 and lack of expression of DcR1 and DcR2, while 8226/MR20 (BCRP) had only low-level expression of DR5. Parental HL60 and 8226 cells displayed dose-dependent cytotoxicity in response to Apo2L/TRAIL. HL60/VCR and HL60/Adr were 3- and 5-fold more resistant to Apo2L/TRAIL than parental HL60 cells, but were not sensitized by the Pgp- and MRP-1-specific modulators PSC-833 and MK571, demonstrating that resistance was not mediated by Pgp and MRP-1. 8226/MR20 (BCRP) cells were not resistant to Apo2L/TRAIL in relation to parental 8226 cells. Of note, cyclosporine A (CsA) sensitized all parental and multidrug resistant cells to Apo2L/TRAIL, lowering IC50’s 2- to 5-fold, likely by a pro-apoptotic mechanism independent of MDR modulation. AML blasts did not express Apo2L/TRAIL receptors, with the exception of DR5 in two samples, both DR5 and DcR1 in one and DcR1 alone in a fourth. Moreover, AML blasts showed minimal or no apoptosis following 24- and 48-hour in vitro exposure to Apo2L/TRAIL in concentrations up to 1 ug/ml, 30-fold higher than the highest cytotoxic concentration in cell lines, and no enhancement of apoptosis by CsA. In conclusion, MDR mediated by ABC proteins does not appear to be associated with Apo2L/TRAIL resistance in cell line models, but AML cells are resistant to Apo2L/TRAIL, and this resistance is associated at least in part with lack of receptor expression. Strategies for upregulating Apo2L/TRAIL receptor expression on AML cells warrant further study.
Frequency and Dynamics of Bcr1/Bcr3 Isoforms of PML/RARA Fusion Gene - Results of Russian APL Multicenter Trial.
Authors: Savchenko Valeri , Parovitchnikova Elena , Demidova Irina , Shuravina Elena , Isaev Valentin , Miyurin Andrey , Kulikov Sergei 
Published: April 2020

Abstract
Detection and monitoring of minimal residual disease (MRD) in APL patients has become a routine practice and is essentially important for tailoring the therapeutical intervention. Two major isoforms of PML-RARa fusion gene (bcr1/2 and bcr3) are considered to determine diverse outcome with bcr3 to be less favorable. It was also shown by different study groups that among different ethnic populations the ratio of bcr1/2 and bcr3 varies. The prevalence of bcr1/2 isoform over bcr3 was reported in Latinos and Chinese population: 84% vs 16% and 73% vs 27%, respectively. Less evident but nevertheless convincing tendency was registered in USA (US Intergroup – 63% vs 37%; Memorial Sloan Kettering CRC – 66% vs 34%), Great Britain (MRC – 61% vs 39%), Italy (GIMEMA – 60% vs 40%), Spain (PETHEMA – 56% vs 44%) (Santillana S. et al Joint International Congress on APL, Rome, 2001, abstr P2.14; Dan Douer et al BJH, 2003, p.563–570). The analysis of PML-RARa transcript in 66 APL patients included in the Russian Multicenter trial revealed the inverse (statistically significant from mentioned above) ratio with 37 patients (56%) bearing bcr3 isoform and 29 (44%) – bcr1/2. There is no exact explanation for these findings but it may be due to low numbers of cases and perhaps to certain environmental and/or ethnic reasons. The treatment results in these 66 APL patients are very similar to usually reported with 7+3+ATRA protocols – 91% CR rate with 75% molecular CR after the first and 96% - after the second course. The OS and DFS do not differ according to the isoform and constitute 77% and 80% at 3 years, respectively. It is worth to stress that close monitoring of MRD (3–15 probes per patient) revealed different time adjusted dynamics in the molecular relapse incidence for bcr1/2 and bcr3 isoform. It was equal at each month during the whole period of follow-up (36 mo from treatment start) for bcr1/2 patients, and clustered in two periods (3–12 mo) and (20–36 mo) for bcr3 patients with 8 months of absence of positive signal. So we may suppose that each isoform of PML-RARa fusion gene determines its distinctive course of MRD while standard APL treatment. This data once again shows discrepancies in the biological features of APL with bcr1/2 and bcr3 isoforms.
Prognostic Significance of FLT3 Mutations in Pediatric Non-Promyelocytic Acute Myeloid Leukemia.
Authors: Kang Hyoung Jin , Hong Seung Hee , Kim In Ho , Park Byung-Kiu , Han Kyou Sup , Cho Han Ik , Shin Hee Young , Ahn Hyo Seop 
Published: April 2020

Abstract
Flt3 is a receptor tyrosine kinase involved in the survival of hematopoietic stem cells and activating mutations of Flt3 were reported to have prognostic significance in AML. This is the first study analyzed the Flt3 mutations in pediatric non-promyelocytic AML patients received same treatment scheme. Total 61 patients received BH-AC, idarubicin, 6-TG, and intrathecal Ara-C as an induction therapy. Once in complete remission (CR), patients with a matched related donor received BMT after two courses of consolidation therapy while those without donor received autologous peripheral blood stem cell transplantation with BCNU, etoposide, Ara-C, and cyclophosphamide conditioning regimen after four courses of consolidation therapy. Flt3 internal tandem duplication (Flt3/ITD) of juxtamembrane domain and D835 mutation (Flt3/D835) of tyrosine kinase domain were analyzed with PCR of genomic DNA. The incidence of Flt/ITD and Flt D835 were 6.6% (4/61) and 3.3% (2/61), respectively. After induction therapy, the CR was archived in 93.4% of the patients and all six patients with Flt3 mutations archived CR. The overall survival and event free survival of all patients were 58.8% and 45.6%, respectively. The disease free survival (DFS) was same as the relapse free survival (48.9%) because all events after CR were relapse. The patients with Flt3/D835 are still alive after autologous peripheral blood stem cell transplantation. The DFS of patients with Flt3/ITD (0%) was lower than that of others (51.9%) significantly (P = 0.0062). Flt3/ITD was the sole adverse prognostic factor for DFS in multivariate analysis (RR=5.6). The patients with Flt3/ITD relapsed very early even after receiving bone marrow transplantation from matched related donor with little BuCy conditioning. New therapeutic scheme such as stem cell transplantation with very intensive conditioning just after complete remission could be applied in pediatric non-promyelocytic AML patients with Flt3/ITD mutation.
Figure Figure
Predictive Value of Cytogenetics on Outcomes of Stem Cell Transplantation in Acute Myeloid Leukemia.
Authors: Park Jinny , Lee Mark H. , Lee Se-Hoon , Park Joon Oh , Kim Kihyun , Jung Chul W. , Kim Won Seok , Park Young Suk , Im Young-Hyuck , Kang Won Ki , Park Keunchil 
Published: April 2020

Abstract
Cytogenetic analysis performed at diagnosis is generally recognized as the single most valuable prognostic factor in AML. Several reports have suggested that cytogenetic characteristics present at diagnosis are associated not only with response to induction therapy for adult AML but also with the outcomes of postremission therapy. Our aim in this study was to examine the relationship of disease karyotypes at diagnosis with the outcomes of stem cell transplantation (SCT) as a postremission therapy in the first remission (CR1) of AML. To describe the differences and similarities used by different cooperative groups and to guide future investigations, the cytogenetic data presented in this study were coded and analyzed using two different classification schemes, SWOG and MRC. Forty-six AML patients younger than 56 years old who had undergone allogeneic or autologous SCT as postremission therapy were analyzed. Patients were categorized into favorable, intermediate, unfavorable, and unknown cytogenetic risk groups based on pretreatment karyotypes according to SWOG and MRC criteria. Prior to SCT, all patients received induction and consolidation chemotherapy consisting of idarubicin and cytarabine. Eight patients died during the median follow-up of 37.8 months (range, 7.6–91.8). The 3-year disease-free survival (DFS) and overall survival (OS) rates were 70.9% and 76.2% for all patients (n = 46). In univariate and multivariate analyses, cytogenetic risk status as grouped by the SWOG criteria was a significant prognostic factor for OS in patients with AML in CR1 who underwent SCT as postremission therapy (P = 0.017, P = 0.009). These data suggest that the pretreatment cytogenetic risk factor is the most valuable prognostic factor for OS in patients with AML in CR1 who undergo SCT as a postremission therapy. In particular, the SWOG criteria are superior in predicting OS and survival in our analysis. However, the unknown risk group in the SWOG criteria and the intermediate risk group in the MRC criteria are heterogeneous, and analyses that are more extensive are required. What is clearly needed is a generally accepted cytogenetic classification system and a leukemia cytogenetic database to provide prognostic scoring and real-time data updates, principally for the less frequent and secondary cytogenetic aberrations. Since the current analysis contains only data from patients who received SCT, this analysis has the possibility of being biased due to selection of patients with good performance and the exclusion of those with early relapses. However, the strengths of this trial included its well-defined eligibility criteria, including pretreatment cytogenetic studies, uniform treatment regimens for induction and postremission therapies, and the time between CR1 and SCT.
The Expression of Fas Antigen (CD 95) on Clonogenic Acute Myeloid Leukemia Cells Correlates with Their In Vitro Sensitivity to Farnesyltransferase Inhibitor (FTI; Zarnestra TM).
Authors: Szostek Marta , Zdzilowska Edyta , Skotnick Aleksander B. 
Published: April 2020

Abstract
The farnesyl transferase inhibitors (FTIs) have demonstrated significant antitumor activities in vitro and in vivo due to their ability to inhibit of Ras- oncogen farnesylation. Besides Ras, there are many other farnesylated proteins in cancer pathways which are potential targets for FTI. In this study, the in vitro effect of the FTI (Zarnestra, Z: provided kindly by Johnson & Johnson Pharmaceutical Research and Development) on clonogenic leukemia cells, expressing CD 34 and Fas were examined. All evaluated patients fullfilled the diagnostic criteria for high-risk AML and demonstrated the CFU-L in vitro growth, or/and expression of CD34 antigen on the myeloblast cells. Bone marrow mononuclear cells from 30 AML patients (M0=3, M1=15, M2=5, M3=1, M4=5, M5=1) were isolated and were plated in serum-free methylcellulose medium with or without growth factors (Methocult, Stem Cell Technologies, Vancouver, Canada) for the 14 days in vitro cultures. The expression of Fas (CD 95) on AML cells were also studied (anti-Fas APO-1, FITC- CD 95, Becton Dickinson, USA) by flow cytometric analysis using Cell Quest Software (Becton Dickinson, USA). MNC incubated with increasing concentrations of Z for 24, 48 and 72 days were analysed for apoptosis (staining for annexin-possitive cells, Annexin V Kit, Pharmingen, USA).
The percentage of Fas positivity was variable (range 20–94%) and was related to the morphologic FAB classification with the highest expression in AML-M1 patients (range 28–94, mean 72%, p&lt;0.01).. No relationship was found between Fas and the CD 34 antigen expression. The in vitro CFU-L growth in the presence of cytokines was observed in 19/30 patients (63%) and 37% patients showed the spontaneous CFU-L or no colony growth of blast cells in the in vitro culture. In the majority of evaluated AML cases, a time and dose dependent proapoptotic in vitro effect of Z was found. The above effect was the most frequent in AML-M1 patients (11/23). Within Z concentration between 20–300 nM, the significant increase of apoptosis cell number (mean 60% AN+/PI− cells) was observed. After 24, 48 and 72 h, incubation with Z the number of patients whose cells underwent apoptosis were 49%, 13% and 8% respectively. The Z induced apoptosis showed significant correlation with Fas expression on AML cells.(P&lt;0.01). The myeloblast apoptotic was not detected in the patients (40 %) demonstrated spontaneous CFU-L growth and the lack of Fas expression on blast cells (even after 120 h Z. exposure).
Our observations suggest that Z induced apoptosis of AML cells might be mediated at least in part by Fas, expressed on primitive, clonogenic leukemic progenitor cells. Induction of apoptosis throught the Fas pathway might be one of the new approach for effective leukemia therapy.
G Protein as Subunit T393C Polymorphism Is Associated with Progression-Free Survival in Chronic Lymphocytic Leukemia.
Authors: Nueckel Holger , Frey Ulrich H. , Duehrsen Ulrich , Siffert Winfried 
Published: April 2020

Abstract
Heterotrimeric G proteins mediate intracellular transduction of many hormone-receptor interactions. Activation of the G protein αs subunit (Gαs) upon stimulation of specific G Protein coupled receptors results in increased levels of the second messenger cAMP which has been shown to induce apoptosis in B-cells. On this background we investigated a potential association of a common silent single-nucleotid polymorphism (T393C) in the gene GNAS1 on chromosome 20 encoding Gαs with disease progression in patients with chronic lymphocytic leukemia (CLL).
We genotyped the DNA from 109 patients with CLL and 100 healthy controls using PCR amplification followed by restriction analysis. Comparing the CLL patients with healthy controls we found no significant differences in allele frequencies or genotype distributions (CLL patients: 393CC 34 vs CT 51 vs TT 24; healthy controls: 393CC 25 vs CT 50 vs TT 25). However, progression-free survival (PFS) was significantly shorter in 393CC patients compared to T393 allele carriers (median PFS CC: 36 months; T-allele: median PFS not reached; log rank test: p=0.029; adjusted for Binet stage) after 5 years observation time. In multivariate analysis the T393C polymorphism was an independent prognostic factor for PFS.
Our data suggest that the GNAS1 T393C polymorphism is not associated with the risk for B-CLL. However, the T393C polymorphism may be a prognostic marker for PFS. It is hypothesized that the 393T-allele is associated with increased cAMP concentrations and, therefore, with higher rates of apoptosis. Further studies assessing differences in the signaling pathway dependent on genotype are underway.
Prognostic Significance of FLT3 ITD and Asp835 Mutations in Patients with Acute Myeloid Leukemia (AML) - a Single Institution Experience.
Authors: Nahajevszky Sarolta , Andrikovics Hajnalka , Lovas Nora , Tordai Attila , Poros Anna 
Published: April 2020

Abstract
Treatment outcome in patients with AML is determined by a variety of prognostic factors such as WBC, LDH, age, presence of chromosomal aberration. Recently, two acquired genetic alterations, internal tandem duplications (ITD) and Asp835 codon mutations of the fms-like tyrosine kinase 3 (FLT3) gene were reported in AML as prognostic factors. 66 consecutive adult patients (39 females and 27 males) were treated with newly diagnosed AML in our institute between January 2002 and June 2004. The median age of onset was 49±15 (range 17–83) years. The gender distribution was 1.44 (female/male). We analyzed FLT3 ITD and Asp835 mutations at the time point of diagnosis by fluorescent PCR and PCR-RFLP methods. ITD was present in 22.7% (15/66) of the patients and Asp835 mutations were detected in 7.6 % (5/66). Two patients carried both mutations. 13 of 15 ITD-positive patients had myelomonocytic or monocytic leukemia (M4 and M5 in the FAB classification system). There was no difference between the numbers of ITD-positive and negative patients in complete remission (10/15 [66.7%] vs. 31/51 [60.8%]). In the ITD-positive patient group, the relapse rate was increased (5/15 [33.3%] vs. 7/51 [13.7%]) however, this difference was statistically not significant. The age of onset was greater than 40 years in all Asp835 mutation-positive patients and in this group, no relapse occurred within the follow-up time. The remission rate (4/5) of this group was high in spite of the old age of onset. The single Asp835-positive patient also carried the ITD mutation and showed primary resistance. Our results are in agreement and confirm earlier observations for the ITD mutation in a different patient population. In our relatively small patient group the Asp835 mutation seemed to have a beneficial effect.
Clinical Significance of AML/ETO Fusion Gene mRNA in Acute Myelogenous Leukemia.
Authors: Master Yungui Wang , Jin Jie , Chen Zhimei , Liang Yi 
Published: April 2020

Abstract
Acute myelogenous leukemia (AML) patients with normal-karyotype may have undetected chromosome aberrant that could affect prognosis. Screening for known AML-specific genetic abnormalities using the reverse transcription polymerase chain reaction (RT-PCR) may help in arriving at a more definitive prognosis. And RT-PCR is the most sensitive method to detect Minimal residual disease (MRD). Nested PCR was a frequently used method to amplify AML1-ETO fusion gene. To further comprehend the relationship between AML1-ETO mRNA expression in AML and its clinical significance in Eastern China. We investigated the prevalence of t(8;21) (q22;q22) and AML1/ETO fusion gene in 461 unselected de novo patients with AML by single RT-PCR and compared the results of cytogenetic analysis with these of RT-PCR. The patients’ median age was 29(1–76).
The results were used in diagnosis of 461 de novo leukemic patients, and 70 AML1-ETO-postive patients were followed up. 107 in 461 patients (23.2%) AML1/ETO was detected by RT-PCR. 98 in 461 patients (21.3%) showed t(8;21) (q22;q22) in karyotype analysis. All patients who had t(8;21) (q22;q22) in conventional karyotyping also showed the gene rearrangement in molecular analysis. The results showed that AML1/ETO mRNA could be expressed in cells from AML-M1, AML-M2 and AML-M4 patients. The complete remission rate in AML1/ETO-positive patients was significantly higher than that in AML1-ETO-negative patients (without M3 subtype patients)[80.4% (86/107) vs 70.6% (191/269)]. The AML1-ETO-postive patients who became negative after chemotherapy had an optimistic outcome, but the patients who demonstrated persistence of AML1-ETO mRNA had a poor prognosis. In chemotherapeutic group, patients whose AML1/ETO expression turning from negative (3 cases) or faint positive (1 case) to positive relapsed later. So PCR becoming positive again indicated relapsing. Only 7 was detected in 48 M2 t(8:21) patients who had been maintaining remission for more than 18 months.
RT-PCR detected the overall AML1-ETO-positive rate in AML was from 6% to 13% in Western country. But our results showed the rate is 23.2%. One reason might be that the patients involved in our observation were younger than those patients involved in other observation group reported.. The other reason, which might be more important, was that the differences between China and Western country in race and region.Our results showed single RT-PCR method was sensitive enough to detect AML1-ETO mRNA. These observations suggest that AML1/ETO mRNA could disappear after chemotherapy or bone marrow transplantation. The patients had a great probability to relapse if the results of RT-PCR are continuously positive or change from negative to positive. So Regular detection is necessary for leukemia patients. We can monitor the minimal residual disease by detecting AML1-ETO mRNA regularly to direct clinical therapy
The Prognostic Importance of Pre and Post Dendritic Cells in Autologous Transplantation for Diffuse Large B Cell Lymphoma.
Authors: Bolwell Brian J. , Pohlman Brad , Andresen Steve , Serafino Sheila , Sobecks Ronald , Kuczkowski Elizabeth , Curtis Julie , Rybicki Lisa , Maciejewski Jarek , Baker Janet , Cherni Kelly , Bernhard Laura , Kalaycio Matt , Hsi Eric , Theil Karl 
Published: April 2020

Abstract
Pre and post transplant dendritic cell (DC) levels may correlate with survival, GVHD, and relapse in allogeneic BMT. Whether they have prognostic importance in autologous peripheral blood progenitor cell (PBPC) is unknown. We prospectively collected pre and post dendritic cell levels, including DC1 and DC2 levels in 53 patients with diffuse large B cell lymphoma (DLBCL) to investigate their potential prognostic importance. Pre-transplant analysis of DC1 and DC2 by flow cytometry was obtained 24 hours prior to the initiation of VP-16 (2 gm/m2) or G-CSF (10 mcg/kg/d) (n=4) for PBPC mobilization; post transplant samples were obtained 6 weeks after transplant. 51 of 53 (96%) were sensitive to chemotherapy at the time of transplant; 34% received prior radiation therapy; 15% had an elevated LDH at transplant. 49 of 53 received VP-16 + G-CSF for stem cell mobilization and 4 patients received G-CSF alone. 98% received a preparative regimen of Bu/Cy/VP and one patient received Busulfan alone. In a univariate analysis, higher numbers of pre-transplant DC1 cells and pre-transplant total DC (DC1 + DC2) cells correlated with improved survival, as shown graphically below:
Figure Figure
Patients received a median CD34+ cell dose of 8.7 x 106/kg. DC values did not correlate with CD34+ cell yield. Post-transplant DC1 (p=0.03), DC2 (p=0.035), and post-transplant total DCs (p=0.04) also correlated with improved survival. In all cases, more DCs was associated with a better outcome. In a multivariable model, pre-transplant total DC number (p=0.028), and a normal LDH at the time of transplant (p=0.017) correlated with improved outcome. Median follow up of surviving patients is 15 months. Of 26 patients with pre-transplant total DC numbers greater than 9.10 x 106/mL, 77% of patients are alive, as compared to 56% of patients with pre-transplant total DC numbers less than 9.10 x 106/mL (n= 27)(p=0.022). The high DC group had fewer relapses and fewer late infections. We conclude that higher pre-transplant total DC numbers are associated with improved outcome in ABMT for DLBCL.