bluuebunny/crossref_metadata_2025_split huggingface dataset:
Arsenic Trioxide Induces Apoptosis in Molt-4 Cell Lines: Caspase 8-Dependent and Caspase 3-Independent.
Authors: Qian Wenbin , Ni Wanmao , Liu Junqing 
Published: October 2019

Abstract
Arsenic Trioxide (As2O3) has been used successfully in the treatment of patients with relapsed or refractory acute promyelocytic leukemia (APL) without severe marrow suppression. Currently, the action of As2O3 on many other hematopoietic malignancies is under investigation. Much evidence has shown that caspase-3 plays essential executing role in apoptosis of many leukemia cell lines. But, the exact mechanism of As2O3-induced apoptosis in Molt-4 cell line which is originated from acute lymphoblastic leukemia is not well understood. Here, we investigate the action of As2O3 on Molt-4 cells and involved mechanism. Significant dose- and time-dependent inhibition of cell growth was observed by MTT assay. Following the treatment of As2O3 for 72 h, As2O3 at 4 μM exhibited 50% inhibition of growth in Molt-4 cells. The effect of As2O3 on the cell cycle was determined in Molt-4 cells by FACS analysis. DNA flow cytometric analysis with three independent experiments indicated that As2O3 induced a G1 and a G2-M phase arrest in Molt-4 cells following 6μM of exposure. Similar results were observed in Molt-4 cells following 2μM and 4μM exposure. These results indicated that As2O3 inhibited the cellular proliferation of Molt-4 cells via a G1 and a G2-M phase arrest of the cell cycle. To confirm and evaluate the induction of apoptosis, we performed the staining of cells with annexin V and PI. As with the percentages of sub-G1 group by FACS analysis, the proportion of apoptotic cells was increased in a dose-and -time dependent manner. Taken together, these results indicate that induction of apoptosis can be another mechanism of the antiproliferative effect of As2O3 besides G1 and G2-M phase arrests of the cell cycle in Molt-4 cells. We subsequently studied the activation of initiator caspase-8 and executioner caspase-3 in Molt-4 cells by Western blotting. Molt-4 cells that had undergone apoptosis on culturing with As2O3 displayed the initial activation of caspase-8 with the appearance of the large cleavage fragment of 43 to 41 kd. Despite the higher basal level of procaspase-3 expression in the Molt-4 cells prior to As2O3 treatment, we were unable to detect cleaved, activated caspase-3 following As2O3 treatment. Next, we checked whether inhibition of caspases-3 could abrogate the proapoptotic effects of As2O3. For this purpose the caspase-3 inhibitor, z-DEVD-fmk, was used. The results shown that addition of z-DEVD-fmk did not rescue Molt-4 cells from apoptosis induced by As2O3. These results clearly differ from other observations made with other leukemia cells and might explain, at least in part, that As2O3 induces apoptosis in Molt-4 cells is caspase 8-Dependent and caspase 3-Independent.
Telomeres and Telomerase in Pediatric Patients with T-Cell Acute Lymphoblastic Leukemia (T-ALL).
Authors: Greil Johann , Kleideiter Elke , Schwab Matthias , Boukamp Petra , Koscielniak Ewa , Bangerter Ute , Klotz Ulrich , Niethammer Dietrich 
Published: October 2019

Abstract
Shortened telomeres and elevated levels of telomerase activity are apparently characteristic features of hematologic neoplasias such as high-grade lymphomas and relapsing leukemia. Thus, their measurement might be useful for monitoring disease conditions or predicting clinical outcome. In order to investigate the potential of telomere length (TRF) and telomerase activity (TA) as prognostic indicator in pediatric patients with T-cell acute lymphoblastic leukemia (T-ALL) we analyzed TRF and TA in samples from 20 patients (age range 2–17.5 years). In addition, as TA is limited by the expression of the telomerase catalytic subunit (hTERT) we analyzed hTERT expression. We found that TRF varied widely (3.5 – 8.1 kb; mean ± SD: 6.4 +/− 1.3 kb) in leukemic cells and was significantly shorter (p<0.0001) than that of age-matched controls (8.3 ± 0.4 kb; n=19). Elevated levels of TA were present in 95% of the leukemic samples. Furthermore, expression of hTERT demonstrated a wide interindividual variability (range 141–424,000 normalized units). A statistically significant association between TA and hTERT expression was not found and TRF, TA and hTERT expression was not associated with the clinical outcome in pediatric T-ALL, thereby limiting their prognostic significance.
Incidence of ZAP70 Positivity in Fresh Samples from Unselected Patients Presenting with a B-Cell Lymphoproliferative Disorder.
Authors: Petrie James A. , Milne Tim , Ebrahim Fatema , Cavenagh Jamie D. , Agrawal Samir G. 
Published: October 2019

Abstract
The expression of ZAP70 has been shown to strongly correlate with unmutated immunoglobulin VH in chronic lymphocytic leukaemia (CLL) cells, which in turn has been shown to distinguish a CLL subgroup of poor prognosis. Retrospective studies have linked ZAP70 expression to a more aggressive clinical course and poorer overall survival in CLL. Previous studies on ZAP70 have largely utilised frozen material. We wanted to avoid the biases of using stored material, potential artefacts of the freeze/thawing process and expand our study beyond CLL. Hence, we analysed ZAP70 by flow cytometry in 184 consecutive cases of B-cell lymphoproliferative disorder (LPD). Only fresh peripheral blood (PB) samples were used. A combination of ZAP 70 (Upstate Biotechnology), CD3 PE and CD56 PE (Coulter Immunotech) antibodies (Ab) were used to exclude the contaminating effects of T and NK cells. CD3 and CD56 staining was followed by fixation and permeabilisation (Dako Intracellular Antigen Kit) and addition of anti-ZAP70 Ab. Indirect labelling of ZAP70 was performed using a secondary conjugate IgG(H+L)-FITC (Southern Biotechnology). Positivity was established at the 20% threshold. 143 cases of CLL were examined for ZAP70 expression: 47 (33%) were positive, with the level of positivity ranging from 20 to 91% (median 41%). Three cases initially ascribed as negative, were subsequently found to be positive upon retesting at a later date. The ZAP70 negative cases of CLL had a median value of 1% (range, 0 – 14%). 41 non CLL cases were examined for ZAP70 expression, mantle cell lymphoma (MCL, 16 cases), hairy cell leukaemia (HCL, 3), diffuse large B-cell lymphoma (2) and 20 cases of B-cell LPD that could not be categorised further. Of these non CLL cases, only 4 were positive for ZAP 70 expression and all of these were cases of MCL (24 – 39% positivity.) The ZAP70 negative cases of MCL had a median value of 0% (range 0–17%). No other non CLL B-cell LPD showed levels of expression &gt;10%. This study of flow cytometric analysis of ZAP70 expression in fresh, presentation PB of all LPDs referred to our laboratory revealed that 33% of CLL and 25% of MCL cases were positive. ZAP70 expression in CLL is bimodal (clearly positive or negative using the 20% threshold) with very few cases in the 10–19% range. No other B-cell LPDs were positive for ZAP70. As ZAP70 testing is now part of our routine LPD panel, ZAP70 positivity provides both diagnostic and prognostic information in CLL, helping to distinguish difficult CLL cases from non CLL (other than MCL). Our 3 cases of changing status may reflect improvements in our protocol or may indicate that ZAP70 status is variable over the course of the disease.
Acute Biphenotypic Leukemia: Single Center Experience of Laboratory Presentation and Review of the Diagnostic Criteria.
Authors: Owaidah Tarek M. , Behani Amal Al , Iqbal Mohammed Anwar , El Kum Nasser , Roberts George T. 
Published: October 2019

Abstract
Biphenotypic Acute Leukemia (BAL) is a rare, newly defined disease in the WHO classification of hematological neoplasms. There is little information about the laboratory presentation, and considerable difficulties exist in reaching a definite diagnosis. In this study, designed to examine the laboratory presentation of BAL, we report a total of 23 (3.4%) out of 676 adult and pediatric leukemia cases referred to our center during the last 4 years.
The mean age at presentation was (21.57 ± 15.59 years; range 1 year – 66 years). There were 14 males. The mean hematological and biochemical parameters were as follows: WBC 68.76 ± 65.18 x 10 9/L, Hemoglobin 94.13 ± 15.13 g/L, Platelets 105.7 ± 104.23 x 10 9/L, and LDH 1351.44 ± 1118.29 u/L. Fourteen patients (60.8%) had mixed morphology of small and large blast cells and seven were M1 and M2 according to FAB criteria.
Using the European Group for Immunological Classification of Leukemia (EGIL) scoring system, all patients had positive Myeloid markers with EGIL scores that ranged from 2.0 – 5.5. Eighteen patients were positive for B-cell markers with scores ranging from 2.0 – 8.5 but only 8 patients were positive for T-cell markers with scores of 0.5 – 4.0. Three patients were positive for markers of the three cell lines. In 7 patients myeloid lineage commitment was also demonstrable by ultrastructural myeloperoxidase. Five patients (22%) had normal cytogenetics. Philadelphia chromosome was positive by karyotype in 3 patients (13%) and MLL gene in 2 (8.7%). Three patients (13%) demonstrated trisomies involving chromosomes 19, 22 and 4, respectively.
Out of the 23 patients, 11 (48%) are alive without disease, 4 had died with leukemia, 3 are alive with disease and 5 had lost follow up.
A Contribution to the Cytogenetic Study of Plasmacytoid Dendritic Cell Acute Leukemia.
Authors: Papadhimitriou Stefanos I. , Paterakis Georgios S. , Kritikou-Griva Elpiniki , Zomas Athanassios , Davea Aggeliki , Goumakou Eleni , Tsakiridou Anastasia A. , Gligori Ioanna , Michalis Eurydike , Anagnostopoulos Nikolaos I. , Georgiakaki Maria 
Published: October 2019

Abstract
BACKGROUND: Plasmacytoid dendritic cell (DC2) acute leukemia is a recently described hematological malignancy with distinct clinical and phenotypic features. Yet, with fewer than 40 cases studied so far, the cytogenetic profile of this entity is still elusive. Previous studies (Leroux et al, 2002) have revealed recurrent chromosomal aberrations affecting certain genomic targets and the analysis of additional cases is expected to clarify whether these aberrations - alone or in combination - may constitute specific markers for the disease.
METHODS: Seven patients with a well-established diagnosis of DC2AL (based on clinical, morphological and phenotypic features) were included in the study. A conventional cytogenetic analysis (CCA) was performed on unstimulated bone marrow cultures. Additionally, the diagnostic marrow smears were studied with interphase fluorescent in-situ hybridization (FISH), using commercially available probes for 5q31, 6q21, 7q31, 9p21 (p16 gene), 9q34, 11q23 (MLL gene), 12p13 (TEL gene), 13q14, 17p13 (p53 gene) and 21q22 (AML1 gene) regions. In case of any abnormal finding, further study was performed with the use of centromeric or other appropriate arm/chromosome enumeration probe to distinguish between region deletion or overrepresentation and numerical aberrations of the carrier arm/chromosome.
RESULTS: An abnormal karyotype (by either CCA or FISH) was documented in all seven cases studied, with most lesions indicating the loss of genomic material. The most common finding was a rearrangement of the 21q22 region (involving the AML1 gene). Deletions of 6q21, 9q34, 11q23, 12p13 and 13q14, trisomy 12 and trisomy of 13q were detected in only one case each. Interestingly, some aberrations, including the three cases of AML1 rearrangement, were missed on CCA, suggesting a submicroscopic abnormality.
CONCLUSIONS: The study failed to define recurrent chromosomal lesions in DC2AL, other than 21q22 rearrangements. Our results point to a possible pathogenetic role of the AML1 gene. Since AML1 is involved in both myeloid and lymphoid malignancies, it makes a reasonable candidate for leukemogenesis also in the case of DC2AL. Additional investigation at the cytogenetic and molecular level is needed to verify this assumption.
AP2 Overexpression: Correlation to a Poor Prognosis in CLL.
Authors: Silva Karina Lani , Vasconcellos Deborah Vidal , de Paula Castro Eric Delfraro , Moellman Arthur Coelho , Dobbin Jane , Maia Raquel Ciuvalschi 
Published: October 2019

Abstract
Inhibitors of apoptosis proteins (IAPs) are a group of structurally related proteins that block apoptosis either by binding and inhibiting caspases or through caspases-independent mechanisms. Overexpression of IAPs has been detected in several types of cancers, including hematological malignancies, and it is correlated with chemotherapeutic resistance. B-cell chronic lymphocytic leukemia (B-CLL) is characterized by the accumulation of mature lymphocytes due to defective apoptosis. During disease progression, many patients acquire resistance to chemotherapeutic drugs, perhaps attributable, in large part, to the defects in programmed cell death. To verify whether IAPs expression could be responsible for chemotherapeutic resistance or disease progression we analyzed, by immunocitochemistry, the expression of c-IAP1, c-IAP2 and XIAP in 30 peripheral blood samples from B-CLL patients (16 samples from untreated patients) and compared it to well-known prognosis factors such as clinical stage (Rai and Binet), lymphocyte doubling time, gender, age and previous chemotherapeutic treatment or not. High levels of c-IAP1 and XIAP expression were not associated with any prognosis factor. On the other hand, interestingly, high levels of c-IAP2 expression were correlated with advanced clinical stage (p = 0,021 and p= 0,031 for Rai and Binet respectively) and previous chemotherapeutic treatment (p = 0,043). Our results suggest that the analysis of c-IAP2 expression in B-CLL cells might be considered a powerful tool as a marker for poor prognostic and disease progression.
Varicella Vaccine (VarilRix) in Children with Acute Lymphoblastic Leukemia.
Authors: Ass Teresa Jackowska , Wasilewski Robert , Górska Elzbieta , Wasik Maria , Loch Teresa 
Published: October 2019

Abstract
Background: To assess the effectiveness of vaccination against varicella in children with acute lymphoblastic leukemia (ALL).
Methods: 105 children without a history of varicella, were qualified for immunization against varicella with VARILRIX (Oka-strain varicella vaccine). 48 children had ALL and 57 were healthy. 25 of the children with ALL were receiving maintenance therapy, 23 children were after chemotherapy.
Results: White blood cells (WBC), lymphocytes, and sub-populations of T- and B-lymphocytes were compared in the healthy and leukemic children before and after vaccination. The ALL children had significantly lower counts of WBC and lymphocytes before vaccination. After vaccination there were no significant differences in the counts of WBC in the healthy and leukemic children. However the ALL children had significantly lower mean counts of lymphocytes. Before vaccination the leukemic children showed a significantly lowered percentage of T-lymphocytes with decreased CD4+ and increased CD8+, what resulted in a lowered CD4 to CD8 ratio. After vaccination, only increased numbers of T CD8+ lymphocytes and a lowered CD4 to CD8 ratio were present while there was no significant difference in CD4. In the healthy and leukemic children alike there was no statistically significant difference between B-lymphocytes (CD 19+) and NK cells.
In 10 children (20%), out of the 48 ALL vaccines, varicelliform rash occurred ~1 month after immunization. No adverse effects we observed in healthy children. Seroconversion to varicella-zoster virus was higher in healthy children and ALL children who had skin rash after vaccination. Two ALL children and three healthy ones had varicella one-two years after the vaccination. Those children received only single vaccine doses (double vaccine doses received children above 12 years).
Conclusion: Varicella vaccine was safe and immunogenic in leukemic children during maintenance and after chemotherapy.
Natriuretic Peptides in Children with Acute Lymphoblastic Leukaemia*.
Authors: Jackowska Teresa , Wasilewski Robert , Golabek Malgorzata , Syczewska Malgorzata 
Published: October 2019

Abstract
Background: Antracyclines (ANTR) are powerful antineoplastic agents and play an important role in treatment of acute lymphoblastic leukaemia (ALL). However, a potential heart damage caused by ANTR in patients who have been cured of cancer may lessen the success of their cure. Dexrazoxane (ICRF-187), a chelator of intracellular iron, has been shown to offer protection against the cardiomyopathic properties of antracyclines. Atrial natriuretic peptide (ANP) levels, especially receptors for proANP (1–98) and plasma brain natriuretic peptide (BNP) levels are markedly increased in cardiac impairment.
Objectives of the study: We aimed to measure the immunoreactive proANP (1–98) and N-terminal proBNP (8–29) (Nt-proBNP) in children with ALL after completion of treatment with ANTR under the protective cover of ICRF-187.
Methods used: Concentration of plasma N-terminal part proANP and NT-proBNP was measured in children by enzyme immunoassay (Biomedica). Median age at diagnosis was 5.5 years.
Results: Mean proANP plasma levels were within the normal range both in girls (1061.2 fmol/ml) and boys (778 fmol/ml). However there was a statistically significant difference between the levels in girls and boys. Mean Nt-proBNP plasma levels were normal - 273.3 fmol/ml in all examined children. Out of the 81 patients 5 (6.2%) had slightly elevated Nt-proBNP levels in comparison with healthy subjects. Nt-proBNP plasma levels were not significantly different in boys (261.0 fmol/ml) in comparison with girls (285.4 fmol/ml).
Conclusion: Our preliminary results suggest that measurement of proANP and Nt-proBNP plasma levels is useful in the detection of subclinical left ventricular dysfunction in children receiving antracycline therapy. Cardioprotection with Dexrazoxane in ALL patients treated with 240mg/m² of ANTR was justified and effective. Further, long term follow-up of the studied patients would be necessary to determine the clinical significance of Nt-proBNP increase.
Identification of B-Cell Translocation Gene 1 as a Biomarker for Monitoring the Remission of Acute Myeloid Leukemia.
Authors: Kim Hyeoung-Joon , Cho Jae-We , Kim Jeong Jung , Park Sung Goo , Lee Do Hee , Park Byoung Chul , Cho Sayeon 
Published: October 2019

Abstract
Acute myeloid leukemia (AML) is a biologically heterogeneous disease of the hematopoietic system characterized by a clonal accumulation of immature blast cells in the bone marrow. In this study, we used a proteomic approach based on two-dimensional electrophoresis and mass spectrometry to search for biomarkers related to the complete remission (CR) state of AML patients. We detected one AML-related protein spot using two-dimensional electrophoresis analysis, which is identified as the B-cell translocation gene 1 (BTC1) protein that belongs to anti-proliferative protein family. In the CR state of AML-m2 and M3 patients, BTG1 protein was upregulated in the bone marrow mononuclear cells. In addition strong BTG1 protein spot was detected in the normal bone marrow mononuclear cells while BTG1 levels in samples from AML-M2 patients in the non-remission state after therapy were not increased compared to those prior to therapy. Overexpression of BTG1 mRNA was also observed in the CR state of all-trans retinoic acid (ATRA)-treated AML-M3 patients and ATRA-treated HL-60 cells. Taken together, these results suggest that BTG1 may play a role in the differentiation process of myeloid cells and thus be a potential treatment-related biomarker for monitoring the remission status of AML-M2 and M3 patients following appropriate therapy.
Adult Patients with Acute Lymphoblastic Leukemia (ALL) and Central Nervous System (CNS) Leukemia at Diagnosis May Attain Durable Complete Remissions (CR). Results from the International ALL Trial (MRC UKALL-XII/ECOG E2993).
Authors: Lazarus Hillard M. , Richards Sue M. , Chopra Raj , Litzow Mark R. , Burnett Alan K. , Wiernik Peter H. , Franklin Ian M. , Tallman Martin S. , Buck G. , Durrant Jill , Rowe Jacob M. , Goldstone Anthony H. 
Published: October 2019

Abstract
In 1993, we initiated an international trial in newly diagnosed adult (age 15–60 years) ALL patients. 1637 patients have been entered and data analyzed as of June 2004. All patients receive two induction phases of therapy and CNS prophylaxis (or therapy if CNS involved) as assessed by lumbar puncture for cytospin. Patients age ≤ 50 yr in CR1 who have a matched-related donor (MRD) undergo an allograft, and the remainder in CR1 are randomized either to an autograft or 4 cycles intensive consolidation and maintenance chemotherapy. Matched unrelated donor (MUD) allograft is an option in Philadelphia chromosome (Ph) positive patients. 46 (3%) patients had CNS leukemia at presentation. Median (range) age was 29 (16–56) years, and 5 were Ph+. Five patients never attained CR1 (3 died early during induction on days 4, 25 and 36). 41/46 (89%) patients attained CR1. 23 patients underwent transplant, 17 in CR1 (10 MRD, 2 MUD, and 5 autografts), while 3 MUD and 3 MRD allografts were performed for > CR1. 31/46 patients died, 12 of leukemia, 8 of infection, 3 of GVHD and 8 other causes. 12 patients died in remission due to infection (5), bleeding (2), GVHD (3), and visceral organ failure (2). 15 patients remain alive, one Ph+ in relapse at 58 mo and 14 (30%) Ph- remain in continuous CR at a median 67 (range: 2–133) mo after diagnosis. Treatments for these 15 long-term survivors were: MRD allograft (6 @ 45,53,63,67,98,120 mo), MUD allograft (1 @ 67 mo; performed in relapse), chemotherapy only (6 @ 2,55,87,98,125,133 mo) and autograft (1 @ 31 mo). In this study we noted a low incidence of CNS leukemia but we cannot exclude avoidance of enrollment due to suspected CNS involvement. Adult Ph- ALL patients with CNS leukemia at diagnosis can attain long-term disease-free survivorship using transplantation as well as conventional chemotherapy.
Therapy (and status) No. Pts Survivors in CR (mo) Induction death 3 Died: no remission (resistant disease) 2 MUD without remission 1 67 MUD in CR1 2 MUD post-relapse 2 MRD in CR1 10 45,53,63,67,98,120 MRD >CR1 3 58 (in relapse) Auto (CR1) 5 31 Chemotherapy (CR1) 18 2,55,87,98,125,133 Total 46