bluuebunny/crossref_metadata_2025_split huggingface dataset:
Effects of Arsenic Trioxide on Protein Kinase C and Cytosolic Calcium in Ventriclar Myocardium of Guinea Pig.
Authors: Zhou Jin , Meng Ran , Meng Lu , Yang Baofeng 
Published: October 2019

Abstract
AIM To clarify the mechanisms of the cardiac side effects of arsenic trioxide (As2O3) in leukemia treatment, the effects of As2O3 on protein kinase C(PKC) and cytosolic calcium ([Ca2+]i) in ventriclar myocardium of guinea pig were investigated.
METHODS Fluo-3/AM fluorescent probe tagged [Ca2+]i of guinea pig’s ventriclar myocardium, detected the [Ca2+]i, by laser confocal microscopy before and after exposed to As2O3. Phosphorus radioisotope assay was used to detect the activity of PKC on cell membrane or in cytoplasm. DNA ladders of ventriclar myocardium in Tyrode’s solution after exposed to As2O3 were evaluated.
RESULTS The cytosolic [Ca2+]i did not change when incubated guinea pig’s ventriclar myocardium in Tyrode’s solution with 0.5μmol•L−1As2O3, after incubated in2μmol•L−1As2O3 for 6min, [Ca2+]i began to increase and was continuous increasing for about 9min. After exposed to 10μmol•L−1As2O3 for less than 3 min, the [Ca2+]i kept on increasing till the end (about 27min) of the examination and could not recover. The increasing of [Ca2+]i could be partly blocked by calcium channel blocking agents—verapamil and nifedipin. The PKC of myocardial cells began to rise after incubated in an As2O3 changing concentration culture media for 3 hours, which initial As2O3 was 10μmol•L−1, and the DNA ladders appeared after incubated in it for10 hours. No DNA ladders appeared when incubated in an As2O3 culture media in which the initial As2O3 concentration was under 5μmol•L−1.
CONCLUSIONS As2O3 can active PKC, increase cytosolic [Ca2+]i and promote apoptosis of myocardial cells. The promoting apoptosis action of As2O3 is closely related to the lasting activation of PKC. The initial action target of As2O3 is cell membrane.
Imatinib (STI571) Induces DNA Damage in BCR/ABL-Expressing Leukemic Cells but Not in Normal Lymphocytes.
Authors: Blasiak Janusz , Drzewoski Jozef , Poplawski Tomasz , Czechowska Agnieszka 
Published: October 2019

Abstract
Imatinib (STI571) is a 2-phenylaminopyrimidine derivative used mostly in the treatment of chronic myeloid leukaemia. It targets specifically the BCR/ABL oncogenic tyrosine kinase, inhibiting its activity. Using the alkaline comet assay we showed that STI571 at concentrations ranging from 0.05 to 2 μM induced DNA damage in human leukemic K562 cells expressing the BCR/ABL oncogene, whereas it had no effect in normal human lymphocytes. Because the extent of DNA damage observed in the neutral and pH 12.1 versions of the comet assay was much lesser than in the alkaline version, we concluded that the drug induced DNA alkali-labile sites rather than strand breaks. Imatinib did not induce DNA strand breaks in the direct interaction with DNA as examined by the plasmid relaxation assay. K562 cells were unable to repair H2O2-induced DNA damage during a 120-min incubation, if they had been preincubated with STI571, whereas normal lymphocytes did so within 60 min. Pre-treatment of K562 cells with vitamins A, C and E reduced the extent of DNA damage evoked by STI571. Similar results brought experiments with the nitrone spin traps POBN and PBN, suggesting that free radicals may be involved in the formation of DNA lesions induced by STI571 in K562 cells. These cells exposed to imatinib and treated with endonuclease III, formamidopyrimidine-DNA glycosylase and 3-methyladenine-DNA glycosylase II, the enzymes recognizing oxidized and alkylated bases, displayed greater extent of DNA damage than those not treated with these enzymes.
Suppression of MLL-AF4 by Small Interfering RNAs Inhibits Proliferation and Induces Apoptosis in T(4;11)-Positive SEM Cells.
Authors: Greil Johann , Thomas Maria , Huenefeld Christian , Vornlocher Hans-Peter , Hadwiger Philipp , Heidenreich Olaf 
Published: October 2019

Abstract
The reciprocal chromosomal translocation t(4;11)(q21;q23) creates the fusion genes MLL-AF4 and AF4-MLL located on derivative chromosome 11 or derivative chromosome 4, respectively. We used small interfering RNAs to suppress the MLL-AF4 fusion gene in the t(4;11)-positive leukaemic cell line SEM. Electroporation of SEM cells with MLL-AF4 siRNAs caused a more than two fold transient decrease in MLL-AF4 mRNA levels, which lasted for three days. The reduction in MLL-AF4 fusion transcript levels were associated with a severely diminished clonogenicity, inhibition of proliferation and of G1-S cell cycle transition and induction of apoptosis. Therefore, MLL-AF4 siRNAs are not only useful to study the functions of MLL-AF4 in leukaemogenesis, but may be also promising agents for novel treatment concepts for t(4;11)-associated leukaemias.
Effects of Protein Tyrosine Kinase, Protein Tyrosine Phosphatase and Protein Kinase C on the Apoptotic Process of Leukemia Cells and Human Cortex Neurons Managed by Arsenic Trioxide.
Authors: Zhou Jin , Meng Ran , Yang Baofeng , Li Baoxin 
Published: October 2019

Abstract
Objective Study on the effects of protein tyrosine kinase, protein tyrosine phosphatase and protein kinase C (PKC)on apoptotic process, observe the changes of cytosolic calcium ([Ca2+]i) of human leukemia cells and cortex neurons after clinical relevant dosage of arsenic trioxide (As2O3) exposure in vitro.
Methods Marked [Ca2+]I of human leukemia cells and cortex neurons with Fluo-3/AM, assayed the changes of [Ca2+]I with laser confocal microscopy in real-time after managed with As2O3 in different concentrations respectively, detected the effects of protein tyrosine kinase, the protein tyrosine phosphatase and the activation of protein kinase C on these changes with confocal microscopy and Phosphorus radioisotope assay. Assayed the DNA ladders of leukemia cells and cortex neurons after exposed in As2O3.
Results As2O3 1μmol/L can increase the [Ca2+]I of NB4 cells remarkably but show no effects on neurons. Vanadate, a kind of protein tyrosine phosphatase inhibitor, can dose-dependently promote the increasing of [Ca2+]I caused by 2, 5, 10μmol/L As2O3.The mean value of total increased rate in 280 seconds after exposed in As2O3 in different concentrations were: 6.5±2.3%, 21.7±2.1 %,49.2±2.5% in NB4 cells, and 6.7±2.1%, 19.4±2.5 %, 52.3±2.7% in cortex neurons respectively. Genistein, a kind of protein tyrosine kinase inhibitor, can dose-dependently decrease the raising of [Ca2+]I caused by 2, 5, 10μmol/L As2O3.The mean value of total inhibited rate in 280 seconds after As2O3 management in different concentrations were 6.7±2.9%, 25.6±2.5 %, 52.2±3.5% in NB4 cells, and 7.8±3.1%, 18.1±2.8%, 51.3±3.3% in cortex neurons respectively. The activation of PKC began when exposed in As2O31μmol/L for 3 h, and keep raising continuously in NB4 cells., DNA ladders appeared after exposed in As2O31μmol/L for 24h. However, no appearances above were found in human cortex neurons. In 2μmol/L As2O3 exposedness, The activation of PKC and DNA ladders appeared in neurons.
Conclusions The phosphorylation and dephosphorylation of protein tyrosine kinase and protein tyrosine phosphatase participated in nonspecific apoptosis signal transduction pathway of As2O3, and accompanied with PKC activation. The [Ca2+] elevation was closely related to PKC increasing activation. The tolerances between leukemia cell and cortex neuron to As2O3 were differ in dosage.
Molecular Detection of Bone Marrow (BM) Involvement in Primary Cutaneous B Cell Non Hodgkin’s Lymphoma (NHL) at Diagnosis.
Authors: Gameiro Paula , Cabeçadas José , Sebastião Marta , Sachse Fernanda , Nolasco Inês D. , Lúcio Paulo J. , Silva Maria G. 
Published: October 2019

Abstract
Although the skin is the second most common site of involvement for extranodal lymphomas, only 20% of cutaneous NHL are of B cell origin. A wide range of B cell lymphomas can occur as primary cutaneous tumors and their clinical course can not always be predicted by histology alone. The incidence and significance of the presence of clonal B cell populations in the BM of affected patients at the time of diagnosis are presently unknown. On another hand, the BIOMED II primers were shown to have a high sensitivity for the detection of clonality in B cell lymphoproliferative disorders. We sought to determine the incidence of occult BM involvement in a series of twelve patients (3 women and 9 men, median age 54.5, 28 to 77 years old) diagnosed with primary cutaneous B cell lymphoma between August 2000 and May 2004, for whom skin biopsies, BM trephine biopsies and aspirates and clinical data were available for review. For that, we investigated the presence of clonal B cell populations in the BM aspirates obtained as part of the initial staging procedures by PCR (employing heteroduplex and GeneScanning analysis), using the BIOMED II primers for the immunoglobulin k light chain (IGK) and the immunoglobulin heavy chain complete and incomplete (IGH) rearrangements. At the same time, a set of amplified gene fragments of known sizes was run as a control of the DNA integrity. Patients’ diagnoses, according to the WHO classification, were marginal zone B cell lymphoma (5 cases), diffuse large B cell lymphoma (5 cases), follicular lymphoma (1 case) and NHL NOS (1 case). In all cases clinical evaluation, CT scans from the thorax, abdomen and pelvis as well as BM trephine biopsies failed to demonstrate extracutaneous involvement by NHL. Moreover, a maximum of 6% of policlonal CD19+ B cells were present in the BM aspirates as evaluated by flow cytometry. In three out of 12 cases (25%) a B cell clonal population was present in the BM, as demonstrated by the presence of an IGH clonal rearrangement detected by heteroduplex and/or GeneScanning analysis; they corresponded to two diffuse large B cell NHL cases and one marginal zone B cell lymphoma. Two of these patients are still under treatment and one (with diffuse large B cell lymphoma) remains in complete remission 9 months after first line therapy. In this small series of patients the detection of clonal B cell rearrangements in the BM analyzed at the time of diagnosis was uncommon; the clinical course of the positive cases did not differ from the whole series. Further follow-up studies are needed to define the significance and prognostic impact of those BM clones in cutaneous B cell NHL patients.
Prognostic Relevance of Gene Expression Using RT-PCR in Diffuse Large B-Cell Lymphoma.
Authors: Kim Hee-Nam , Lee Je-Jung , Yang Deok-Hwan , Kim Yeo-Kyeoung , Kim Nan Young , Park Kyeong-Soo , Kim Hyo-Jung , Jang Dae-Young , Ahn Jin-Seok , Bae Sung-Hwa , Ryoo Hun-Mo , Kim Hyeoung-Joon 
Published: October 2019

Abstract
Diffuse large B-cell lymphoma (DLBCL) is characterized by a marked degree of morphologic and clinical heterogeneity. Recently, Rosenwalt et al. (N Engl J Med 2002) reported that four gene expression “signature”, 17 genes were identified as correlated with patient outcome by DNA microarray in DLBCL. In this study, we aim to establish predictor of outcome could help to identify patients who may benefit from risk-adjusted therapies in advance. To do it, we evaluate the prognostic relevance of 17 gene expressions in 72 patients with DLBCL who received a conventional chemotherapy. Seventeen genes were studied using RT-PCR assay from paraffin-embedded sections at the time of diagnosis. The median age of the patients was 58 years (range: 21–80 years). When we initially exam an appropriative patient’s selection for survival analysis, overall survival (OS) at 2 years in patients with the international prognostic index (IPI) < 2 and IPI ≥ 2 were 95.2±4.6% and 50.6±11.8%, respectively (p = 0.009), and progression free survival (PFS) at 2 years in patients with the IPI < 2 and IPI ≥ 2 were 75.0±9.7% and 46.7±12.9%, respectively (p = 0.049). Of the 17 genes, patients with uPA expression showed a shorter OS compared with those without the gene expression. Additionally, patients with the expression of NPM3, uPA, fibronectin, or IMAGE814622 showed a shorter PFS compared with those without the gene expressions. In conclusion, these findings suggest that the gene expression profiling with simple RT-PCR assay is useful for analysis of the prognostic implications in patients with DLBCL.
Bim-EL, Is Sensitive to Proteasome Degradation and Contributes to Inducing Apoptosis after In Vitro Imatinib Mesylate Treatment of BCR-ABL Positive Cells.
Authors: Belloc Francis , Boyer Catherine , Lacombe Francis , Praloran Vincent , Mahon François-Xavier 
Published: October 2019

Abstract
Chronic myeloid leukemia (CML) is a malignant disease of pluripotent hematopoietic stem cells and is characterized by excessive accumulation of the myeloid lineage. The causative event in the initiation of CML is the translocation of the abl gene in continuity with the bcr gene resulting in a fusion gene encoding for a Bcr-Abl tyrosine kinase. The expression of Bcr-Abl protects hematopoietic cells against apoptosis. We investigated the survival pathways triggered by Bcr-Abl. Apoptosis was measured in two cell lines expressing the Bcr-Abl protein either constitutively (K562) or ectopically (BaF/Bcr-Abl). Imatinib mesylate, an inhibitor of the tyrosine kinase activity of Bcr-Abl, induced apoptosis and caspase activation in K562 and BaF/Bcr-Abl and this effect was almost completely inhibited by cycloheximide (CHX) indicating that imatinib needs de novo protein synthesis to induce apoptosis in Bcr-Abl cell lines. MG132, a proteasome inhibitor, was also found to induce apoptosis in both cell lines, an effect also inhibited by CHX. By measuring mitochondrial membrane potential we found that CHX affected the apoptotic process induced by both inhibitors upstream of the mitochondrial step. Co-treatment with imatinib and MG132 failed to show any additive effect and imatinib did not inhibit proteasome activity by itself. These results are in agreement with Bcr-Abl tyrosine kinase exerting its anti-apoptotic effect by driving the degradation of a pro-apoptotic protein with a high turnover which, after phosphorylation, became a substrate for the proteasome. When protein kinase C was activated by PMA, Bim-EL, a pro-apoptotic, BH3-only member of the Bcl-2 family, was converted in its phosphorylated form and its cell content was decreased by 60%. The phosphorylated form of Bim-EL was preserved when proteasome was inhibited by MG132 inducing a two times increase in Bim-EL protein content. Similarly, the content in Bim-EL was increased (three times in K562 and five times in BaF/Bcr-Abl) after 18h imatinib treatment. In this case, Bim-EL accumulated in an un-phosphorylated form and this accumulation was inhibited by CHX. Thus, Bcr-Abl kinase could indirectly drive the phosphorylation of Bim-EL, maintaining its degradation by the proteasome and, consequently, a low apoptotic potential for the cell. Conversely, Bim-EL accumulation could play a crucial role in the apoptotic response of Bcr-Abl expressing cells treated by either imatinib or proteasome inhibitors.
Association of Hydroxyurea to Imatinib Is Effective in Patients with Chronic Myelogenous Leukemia Resistant to Imatinib Alone.
Authors: Latagliata Roberto , Breccia Massimo , Carmosino Ida , Sarlo Chiara , De Cuia Rosa , Mancini Marco , Biondo Francesca , Russo Eleonora , De Vellis Annalisa , Diverio Daniela , Mandelli Franco , Alimena Giuliana 
Published: October 2019

Abstract
The introduction of Imatinib in the treatment of Chronic Myelogenous Leukemia (CML) leads to the achievement of Complete Cytogenetic Response (CCR) in about 70% of patients: however, in the remaining 30% of patients there is a persistance of Ph+ cells also after standard (400 mg/day) and increased (600 mg/day) dose of Imatinib. These patients are thus cytogenetically resistant to Imatinib alone and their management is at present unclear. From 11/2002 to 11/2003, 10 patients in chronic phase (6 male and 4 female, median age 52.5 years, range 29 – 68 years) with persistance of 100% Ph+ cells (9 patients) or BCR/ABL + cells (1 patient with Ph- BCR/ABL+ CML at onset) after standard (at least 6 months of treatment) followed by increased dose (at least 3 months of treatment) of Imatinib alone, were considered resistant and added Hydroxyurea (HU) to Imatinib. Seven patients have been pretreated with IFN before Imatinib; median times from diagnosis and from Imatinib treatment to HU addition were 51 months (range 23 – 151) and 14 months (range 10 – 31), respectively. HU was given according to WBC count: patients with WBC < 10 x 109/l started HU at the dose of 1 g/day, patients with WBC > 10 x 109/l at the dose of 1.5 g/day. Imatinib was continued at the same previous dosage (600 mg/day in 6 patients and 400 mg/day in 4 patients who did not tolerate increased dosage for hematological toxicity). Three patients achieved a complete response (2 CCR after 3 and 12 months respectively and 1 molecular complete response after 9 months in the patient Ph- BCR/ABL+ at onset) and 1 patient achieved a partial CR (Ph+ < 33%) after 9 months: the remaining 6 patients were resistant with persistance of 100% Ph+ cells. Toxicity was mild and only 1 patient discontinued for 2 weeks the association due to transient thrombocytopenia: no extra-hematological toxicity has been recorded. After a median follow-up of 14 months (range 20 – 10), 2 patients (1 resistant and 1 after 5 months from the achievement of CCR) evolved in Blastic Phase (BP), 5 patients are in stable chronic phase with 100% Ph+ cells and 3 patients are still in response after 4,6 and 7 months respectively. In conclusion, the association of HU with Imatinib seems capable to induce cytogenetic response in at least one third of patients resistant to Imatinib alone, with minimal toxicity: a longer follow-up and a comparison with other associations is needed to evaluate the quality and duration of response in such group of patients.
Plasma Adiponectin Concentrations in Relation to Chronic Lymphocytic Leukemia and Chronic Myeloproliferative Diseases.
Authors: Avcu Ferit , Ural Ali U. , Yilmaz Mahmut I. , Bingol Necati , Nevruz Oral , Caglar Kayser 
Published: October 2019

Abstract
Adiponectin, an adipocyte-secreted hormone, is closely and inversely associated with insulin resistance. Adiponectin suppresses the expression of adhesion molecules in vascular endothelial cells and cytokine production from monocytes/macrophages, thus inhibiting the inflammatory processes. In addition, it is an important negative regulator in immune systems and hematopoiesis that suppressed colony formation from colony forming unit granulocyte and macrophage. For these immunological effects of adiponectin, we hypothesized that decreased adiponectin levels might underlie the association between chronic lymphocytic leukemia (CLL) and chronic myeloproliferative diseases (CMPD), and investigated the levels of adiponectin in patients with 19 CLL and 30 CMPD (14 chronic myelogenous leukemia, 9 polycythemia vera, 4 myelofibrosis, 2 essential thrombocythemia), and compared with age, sex, body mass index match controls. Adiponectin levels in patients with CLL were significantly lower than the controls (4.71±1.33 μg/ml vs. 16.61±3.91 μg/ml; p<0.001). Also, the levels of adiponectin in patients with CMPD were significantly lower than the controls (8.95±2.64μg/ml vs. 17.16±4.77 μg/ml; p<0.001). According to the comparison of interferon (IFN) therapy and non-IFN therapy of the patients with CMPD, plasma adiponectin levels in IFN therapy patients were significantly higher than in non-IFN therapy patients (11.03±1.39μg/ml vs. 6.87±1.79 μg/ml; p<0.001). The results show that adiponectin is lower in patients with both CML and CMPD. These results suggest that lymphopoiesis and myelopoiesis is negatively influence of adiponectin level and its possible role may be related with inflammatory cytokine (eg: TNF, IL-6) release. Also, IFN therapy that suppressed of inflammatory cytokines in patients with CMPD is positively influenced of adiponectin secretion. Future studies are needed to prove causality and provide insight on the mechanism of action of this hormone and its potential role in CML and CMPD.
B-Chronic Lymphocytic Leukemia (B-CLL), Small Lymphocytic Lymphoma (SLL) and Waldenstrom’s Macroglobulinemia (MW): A Comparative Fish Analysis.
Authors: Dimopoulou Maria N. , Angelopoulou Maria K. , Vassilakopoulos Theodoros P. , Kyrtsonis Marie-Christine , Koumbis Dafni , Kontopidou Flora N. , Siakantaris Marina P. , Kalpadakis Christine , Kokoris Styliani I. , Dimitriadou Evangelia , Pangalis Gerassimos A. 
Published: October 2019

Abstract
Chromosomal abnormalities in B-CLL are considered as potent prognostic factors. In other small lymphocytic disorders, closely related to B-CLL, such as SLL and MW the cytogenetic profile has not been extensively studied. The purpose of the present study is to identify any potential differences in chromosomal abnormalities between B-CLL, SLL and MW. We studied 24 consecutive B-CLL, 13 SLL and 8 MW patients diagnosed in our Unit. Diagnosis was based on standard morphologic and immunophenotypic criteria for B-CLL and SLL patients. Cases with absolute lymphocyte count < 5x 109/L were considered as SLL. The diagnosis of MW was established in the presence of serum monoclonal IgM and lymphocytic/lymphoplasmacytic infiltration of the bone marrow. Separated lymphocytes from peripheral blood (B-CLL) or bone marrow (SLL and MW) were fixed and FISH analysis for trisomy 12 and 13q deletion was performed according to standard techniques. 200 intact interphase nuclei were scored for each sample. Cut-off levels were defined by the mean value plus 3 standard deviations of the frequency of the abnormalities in 10 normal controls. 5/24 B-CLL cases were positive for trisomy 12 (21%) versus 6/12 (50%) SLL and 0/7 (0%) MW cases. Del 13q was found in 8/14 (57%) of B-CLL, versus 1/6 (17%) of SLL and 0/8 (0%) of MW patients. We found a difference in the cytogenetic profile between B-CLL and SLL, which represent two closely related entities with different tissue localization pattern. Thus trisomy 12 was more frequently observed in SLL, whereas the opposite was true for del 13q. In addition none of these two chromosomal abnormalities was encountered in MW, a finding that could potentially serve as an additional tool for the differential diagnosis between these related disorders. These findings need to be confirmed in larger series of patients and their biologic significance should be further investigated.