bluuebunny/crossref_metadata_2025_split huggingface dataset:
Thalidomide-Associated Thromboembolism in Cancer: Reimbursement for Thalidomide’s “Off-Label” Prescribing under the 2004 Medicare Oral Pharmaceutical Demonstration Project Raises Concerns.
Authors: Evens Andrew M. , McKoy June M. , Yarnold Paul R. , McCaffrey Kathyrn , Bennett Charles L. 
Published: October 2019

Abstract
Purpose: In 1999, one year after its approval by the FDA for erythema nodosum leprosum, thalidomide’s effectiveness as an off-label treatment for multiple myeloma was noted. A 28% rate of thromboembolism with thalidomide-doxorubicin therapy for myeloma was reported in 2001. Thalidomide’s inclusion in the 2004 Medicare Oral Pharmaceutical Demonstration Project as treatment for multiple myeloma represents the only off-label use drug covered. FDA regulations prohibit manufacturer dissemination of comprehensive safety information describing thalidomide-associated thromboembolism (TAT) in the off-label oncology setting. Herein, we reviewed FDA and published information for TAT in the oncology setting.
Methods: Adverse event reports contained in FDA databases (n= 190 patients) and 48 prospective clinical trials (n= 2,329 patients) were reviewed for information on thromboembolism occurring among thalidomide-treated cancer patients.
Results: TAT occurred after a median of 52 days of therapy (range, 6 to 469 days), with more than half of these events among persons with multiple myeloma. TAT rates of 30% were noted among patients with newly diagnosed multiple myeloma receiving concomitant doxorubicin. Previously treated myeloma patients receiving thalidomide and doxorubicin and newly diagnosed patients on thalidomide, doxorubicin, and low molecular weight heparin had thromboembolism rates of 15% or lower.
Conclusions: Revision of FDA regulations to allow dissemination of information describing benefits and toxicities of thalidomide as an off-label cancer treatment is important, particularly for multiple myeloma patients receiving thalidomide under the 2004 Medicare Oral Pharmaceutical Demonstration Project.
Cancer drugs covered under the Medicare Replacement Drug Demonstration Project CANCER INDICATION ONCOLOGY DRUG Breast cancer Anastrazole Breast cancer Exemestrane Breast cancer Letrozole Breast cancer Tamoxifen Breast cancer Toremifene Chronic myelogenous leukemia Imatinib mesylate Cutaneous T-cell lymphoma Bexarotene Epithelial ovarian cancer Altretamine GI Stromal Tumor Imatinib mesylate Multiple myeloma Thalidomide Non-small cell lung cancer Gefitinib Non-small cell lung cancer Erlotinib Prophylaxis for ifosfamide-induced hemorrhagic cystitis Mesna
Gene Expression Profile of Nodal vs Extranodal Diffuse Large B-Cell Lymphoma from Saudi Arabia.
Authors: Jehan Zeenath , Siraj Abdul Khalid , Simon Ronald , Sauter Guido , Kuraya Khawla A.l. 
Published: October 2019

Abstract
Diffuse large B-cell lymphoma (DLBCL) belongs to the most common malignancies in Saudi Arabia, accounting for 50–60% of adult non-Hodgkin Lymphomas. DLBCL represents a heterogeneous group of tumors with respect to morphology, genetics, and clinical behaviour. The two major subtypes of DLBCL differ in their site of origin, i.e. within (nodal) or outside (extranodal) the lymph nodes, and a separate genetic pathway has been suggested for these subtypes. To detect potential biological differences between these two DLBCL categories, we performed gene expression analysis in 20 nodal and 8 extranodal lymphoma tissues, as well as in 4 normal lymph nodes, using the GeneChip technology (Affymetrix HG-U133_2 array). Data analysis using the D chip software highlighted a total of 215 genes expression patterns of which were significantly different in nodal and extranodal lymphomas. The most striking differences were observed for genes contributing in ATP binding (20 genes), nucleotide binding (12 genes), response to stress (19 genes), RNA metabolism (6 genes), protein translation (4 genes), and inflammatory response (4 genes). Remarkably, also 5 protein tyrosine kinases were found to be differentially expressed. Our data strongly suggests the existence of at least two different genetic pathways for the development of nodal and extranodal DLBCL, which are characterized by these genetic changes. These results prompt for further expression analysis in large cohorts of histomorphologically well defined lymphoma tissues in order to evaluate the clinical relevance of these alterations.
Lack of PRDM1α Expression in Hodgkin/Reed-Sternberg Cells Is Likely Mediated by a Translational or Post-Translational Mechanism.
Authors: Tam Wayne , Tan Leonard , Gomez Mario , Fan Shaoan , Liu Yifang , Wright Kenneth , Chadburn Amy , Knowles Daniel M. 
Published: October 2019

Abstract
Hodgkin/Reed Sternberg (H/RS) cells are the neoplastic cells in classical Hodgkin lymphoma (HL). They are thought to resemble post-germinal center (GC) B cells with expression of markers associated with late stage of B-cell differentiation, for example, interferon regulatory factor -4/multiple myeloma-1 (IRF4/MUM1) and syndecan 1 (CD138). The PR (PRDI-BF1-RIZ) domain zinc finger protein 1 (PRDM1), a transcription repressor with a master regulatory role in plasma cell differentiation, is normally co-expressed with IRF-4/MUM-1 in plasma cells and in a subset of activated GC cells committed to plasma cell fate. We studied expression of PRDM1α, the functional isoform of PRDM1, in 14 classical HL cases [including 3 positive for Epstein-Barr-virus (EBV)] and 4 HL cell lines by immunohistochemistry and Western blotting, respectively. H/RS cells in primary HL cases are negative for PRDM1α, implying a desynchrony in expression between IRF-4/MUM1 and PRDM1. While the myeloma cell line U266 expresses relatively abundant PRDM1α, it was undetectable by Western Blotting in all HL cell lines tested, except for the EBV-positive HL cell line L591 which, unlike in vivo H/RS cells, has a Type III EBV latency pattern. PRDM1α expression in L591 but not in vivo H/RS cells suggests that PRDM1 expression may be modulated by latency type-specific EBV-encoded gene products or the B-cell phenotype exhibited by the cell line. The lack of PRDM1α protein in H/RS cells is not due to impaired gene transcription, since real-time quantitative PCR revealed similarly abundant PRDM1α transcripts in the HL cell lines as U266. In the absence of mutation in the PRDM1 coding region, these results suggest that failure to accumulate PRDM1α protein in H/RS cells is likely due to abnormal translation repression or protein turnover. Loss of functional PRDM1 as a result of translational or post-translational deregulation may represent a novel molecular lesion in HL.
BCR/ABL Post-Translationally Enhances hnRNP E2 Expression and Translation-Inhibitory Function through the Activation of ERK1/2 Mitogen-Activated Protein Kinases.
Authors: Chang Ji-Suk , Notari Mario , Marcucci Guido , Perrotti Danilo 
Published: October 2019

Abstract
Impaired differentiation is a common feature of many hematological malignancies including blast crisis chronic myelogenous leukemia (CML-BC). We previously reported that expression of the RNA binding protein hnRNP E2 is enhanced in CML-BC patient samples by the activity of BCR/ABL oncogenic kinase which uses hnRNP E2 to suppress translation of C/EBP alpha, the main regulator or granulocytic differentiation. Here we show that hnRNP E2 protein but not mRNA expression correlates with BCR/ABL levels in mouse 32Dcl3 myeloid progenitor cell clones expressing different levels of p210 BCR/ABL, and in the BCR/ABL-inducible TonB.210 cell line. Furthermore, exposure of 32D-BCR/ABL cells to imatinib or to the HSP90 inhibitor 17-AAG, which induces BCR/ABL proteasome-dependent degradation, results in downregulation of hnRNP E2 protein levels. Mechanistically, it appears that increased hnRNP E2 expression depends on BCR/ABL-induced post-translational modifications that increase hnRNP E2 protein stability and prevent its proteasome-dependent degradation. Indeed, we have evidence that hnRNP E2 is associated with PRMT5 arginine-methyltransferase and undergoes phosphorylation in K562 cells. Accordingly, inhibition of the mitogen activated ERK1/2 kinases by PD098059 and U0126 reduces hnRNP E2 levels and, in turn, hnRNP E2 binding to the C-rich element contained in the uORF of c/ebp alpha mRNA. Thus, activation of MAPK might be required for the hnRNP E2-dependent suppression of myeloid maturation in CML-BC.
Effect of p53 Silencing on Asenic Tioxide-Induced Apoptotic Pathways in a Myeloma Cell Line Expressing w.t.p53.
Authors: Fatih Kircelli , Cagla Akay , Yair Gazitt 
Published: October 2019

Abstract
Mutations in the p53 gene are the most common genetic abnormality in human cancers. P53 is a tumor suppressor gene, which regulates a wide variety of target genes controlling cell cycle and apoptosis. Arsenic Trioxide (ATO) is an effective chemotherapeutic agent for the treatment of acute promyelocytic leukemia and is being tested in phase II studies in various types of hematological malignancies and solid tumors. We have previously shown that ATO is a potent inducer of apoptosis in multiple myeloma cells, engaging the intrinsic apoptotic pathway in cells expressing w.t. p53. In contrast, in cells expressing mutant p53, both the intrinsic and extrinsic apoptotic pathways are engaged. Our finding in this respect were further supported by our recent study using a p53 temperature sensitive (p53Ts) mutant cell line, BRK, expressing w.t. p53 at 32°C and mutant p53 phenotype at 37°C (Akay et al.,AACR; Abstract #5344, 2005). We hypothesized that knocking out of p53 or p21 mRNA will result in modifying ATO-induced apoptotic pathways as observed using the p53-Ts conditional mutant of BRK cells. Thus, IM9 cells (expressing w.t.p53) were transfected [AMAXA Nucleoporator, ~60% transfection by green fluorescence protein (GFP) tag] with a GFP-SiRNA expressing plasmid co-expressing anti-sense RNA sequences for p53 (GFP/Sip53) and p21 (GFP/Sip21). As a control, GFP expressing plasmid not containing SiRNA (GFP/cont) was used. We observed in GFP/cont-transfected cells a G1 arrest through activation of p21 and moderate apoptosis, primarily through activation of procaspase 9, with no activation of BID and procaspase 8. In cells transfected with GFP/Sip53 or GFP/Sip21 plasmids we observed rapid mitochondrial membrane depolarization and apoptosis primarily through activation of the extrinsic apoptotic pathway with downregulation of FLIP, activation of procaspase 8 and BID, enhanced release of AIF from mitochondria and rapid apoptosis. Depletion of glutathione was observed with or without silencing of p21 or p53. Furthermore, silencing of p53 or p21 resulted with a decrease in ATO-induced activation of c-jun and Erk and in a decrease in the activation of Akt. These results further substantiate the model we put forward for the role of p53 in ATO-induced apoptosis in myeloma and other cancer cell lines.
BCR/ABL Oncogene Controls MICA Translation.
Authors: Boissel Nicolas , Rea Delphine , Tieng Vannary , Dulphy Nicolas , Brun Manuel , Cayuela Jean-Michel , Rousselot Philippe , Tamouza Ryad , Le Bouteiller Philippe , Mahon François-Xavier , Steinle Alexander , Charron Dominique , Dombret Hervé , Toubert Antoine 
Published: October 2019

Abstract
MHC class I chain-related molecules (MIC) participate in immune surveillance of cancer through the engagement of NKG2D, an activating receptor on NK and T-cells. However, the release of soluble forms of MIC (sMIC) by the tumor may impair this response by decreasing NKG2D surface expression. The molecular basis for MIC expression in tumors is poorly understood. In chronic myeloid leukemia (CML), a malignancy caused by the BCR/ABL fusion oncoprotein., leukemic hematopoietic CD34+ cells expressed MICA at the cell surface, whereas hematopoietic CD34+ cells from healthy donors did not. At diagnosis, CML patients showed increased serum levels of sMICA and a decreased NKG2D expression on NK and CD8+ T-cells. Upon imatinib mesylate (IM) therapy, a specific BCR/ABL inhibitor, serum sMICA and NKG2D expression returned to normal levels. In BCR/ABL positive K562 cell line, IM decreased both surface MICA/B expression and NKG2D-mediated lysis by NK cells. Silencing BCR/ABL gene expression directly evidenced its role in the control of MICA expression. IM did not affect MICA mRNA levels but decreased MICA protein expression and sMICA release. Sucrose density gradient fractionation of cytoplasmic extracts from K562 treated with IM showed a shift in the distribution of MICA mRNA from the polysomal toward the monosomal fractions, favoring a decreased translation. Among the major pathways activated by BCR/ABL that regulate translation, PI3K and mTOR were shown to also control MICA expression. These data provide evidence for a direct control of MICA expression by BCR/ABL oncogene and indicate that post-transcriptional mechanisms may participate to the regulation of MICA expression.
Expression of ERK1/ERK2 MAP Kinase, Protein Kinase C and Akt Kinase by Lymphoid Malignant Cells.
Authors: Murohashi Ikuo , Takahashi Takashi , Ihara Noriko , Wakao Daisuke , Yagasaki Fumiharu , Nakamura Yhuichi , Kawai Nobutaka , Matsuda Akira , Jinnai Itsuro , Bessho Masami 
Published: October 2019

Abstract
ERK1/ERK2 MAP kinase (MAPK), protein kinase C (PKC) and Akt kinase have been shown to inhibit cellular apoptosis. We measured the expression levels of these protein kinases in a total of 102 samples from patients with lymphoid malignancies: 26 with acute lymphoblastic leukemia (ALL), 15 with multiple myeloma (MM), 49 with non-Hodgkin’s lymphoma (NHL), 3 with Hodgkin’s lymphoma (HL) and 6 with chronic lymphocytic leukemia (CLL). Plasma cells were separated by using magnetically labeled CD138, and the purity of the cells were more than 95%. The MAPK and PKC assay systems are based upon the enzyme catalyzed transfer of the [γ-32P] ATP to a specific peptide. Activity of Akt kinase was measured by Western blotting using phospho-specific Akt (Ser 473) antibody. MAPK activity was 0.4±0.0, 4.7±0.7 and 19.0±21.6 p mol/min/106 cells in normal blood mononuclear cells (n=3), normal bone marrow plasma cells (n=10), and patient samples (n=85), respectively. MAPK and PKC activities were 17.1±10.5 and 50.7±58.3 p mol/min/106 cells in ALL, 29.3±39.3 and 29.1±18.9 in MM, 17.3±16.4 and 46.5±46.7 in NHL, 13.6±3.2 and 4.0±3.2 in HL, and 7.3±4.8 and 2.2±0.2 in CLL, respectively. MAPK activity of CLL was significantly low (P<0.05) compared with that of ALL. Phosphorylated Akt was detected in 57 of 59 (97%) patients examined. A significant positive correlation between the activities of PKC and Akt kinase, but not those of MAPK and PKC or MAPK and Akt kinase, was noted. Kaplan-Meier estimates of overall survival (OS) revealed that the OS of the MM patients with lower MAPK was better than those with higher MAPK, although the difference was not significant (P = 0.15). OS was not different by MAPK for ALL or NHL, and by PKC for ALL, MM, or NHL. Effects of various cytokines on the MAPK activity of malignant lymphoid cells in serum free culture were examined. IL-7 significantly enhanced the MAPK activity in 46% of ALL patients, IL-15 in 31% of NHL patients, and IL-15 and IL-6 in 38% and 35% of MM patients, respectively. Taken together, our results suggest that MAPK activity is significantly and markedly elevated and that MAPK may play important roles by various subtype of lymphoid malignancies.
Chromosomal Instability Induced by Overexpression of Telomere Repeats Binding Factor 1.
Authors: Lan Jianping , Huang He , Zhu Yuanyuan , Yu Jian , Sun Jie 
Published: October 2019

Abstract
Telomere dysfunction has been associated with chromosomal stability in process of oncogenesis. Telomere, a special nucleoprotein complex at the termini of linear eukaryotic chromosomes, functions to prevent chromosomes from degradation by endogenous nucleases, fusion and recombination of chromosome ends, triggering DNA damage response and checkpoint-induced cell cycle arrest or apoptosis. Telomere homoeostasis and length are maintained by a set of telomere binding proteins. Among these, telomere repeats binding factor 1(TRF1) serves as a negative regulator of telomere length since TRF1 overexpression would elicit the shortening of telomere length in telomerase-positive cells. To date, the expression level of TRF1 in human cancers remains controversial and its role and mechanism in tumorigenesis are poorly understood. To answer these questions, we introduced EGFP-tagged TRF1 plasmid into HeLa cells to establish a stable cell line with TRF1 overexpression. Positive clones were selected by G418(1mg/ml) and GFP fusion protein was confirmed by immunoblotting analysis with anti-GFP antibodies. Interestingly, these cells demonstrated a higher percentage of mitotic abnormality including chromosome misalignment, anaphase bridging, lagging chromosome and multipolar spindles than controls after over 10 passages(20.0% vs 1.5%, p<0.01). To further clarify if this phenomenon resulted from chromosomal fusion, metaphase chromosome spreads were prepared. As expected, the TRF1 stable cells showed an elevated frequency of dicentric chromosomes compared with untransfected cells, which implicated chromosomal end-to-end fusion in these cells. Our results suggested high expression of TRF1 would induce chromosome missegregation at mitosis, a feature of chromosomal instability which is proposed to be a critical step in carcinogenesis. These findings bring fourth a new hint for our further understanding of carcinogenesis led by telomere dysfunction.
TNFα Stimulates NKG2D-Mediated Lytic Activity of Acute Myeloid Leukemic Cells.
Authors: Laurent Guy , Guilloton Fabien , de Thonel Aurelie , Jean Christine , Demur Cecile , De Mas Veronique , Quillet-Mary Anne 
Published: October 2019

Abstract
The mechanism by which leukemic cells interfere with normal hematopoiesis remains unclear. We show that, whereas the leukemic KG1a cells are naturally devoid from cellular cytotoxicity, once activated by TNFα, they display cytolytic activity towards various cellular targets including CFU-GM. This mechanism is dependent on stimulation of Granzyme B/Perforin system. In addition, KG1a cells expressed the NKG2D receptor and its signal-transducing adaptator DAP10, which were functional as confirmed by redirected lysis experiments. Interestingly, flow cytometry analysis of 20 samples of patient with acute myeloid leukemia (AML) (FAB M0 to M5) revealed the expression of NKG2D (40%) and other natural cytotoxicity receptors (40% for NKp30, 74% for NKp44, 39% for NKp46) by pool >15% of leukemic cells. Futhermore, CD34+ hematopoietic progenitors undergoing granulo-monocytic differentiation expressed NKG2D ligands. Altogether, we propose a model in which upon stimulation by TNFα leukemic cells may exert cytotoxicity against myeloid progenitors. This finding may have important clinical implications in the context of diseases characterized by TNFα accumulation, such as AML or myelodisplasic syndromes.
The Effects of Berbamine in Nude Mice Xenograft Model of Human Leukemic Cells.
Authors: Wu Dong , Lin Maofang 
Published: October 2019

Abstract
Background: Berbamine is a kind of bis-benzylisoquinoline extracted from Chinese herb. In our past research, it had been proven that berbamine could obviously inhibit the proliferation and induce apoptosis in different kinds of leukemic cell lines including K562, Jurkat, NB4 in a time-and dosage-dependent manner in vitro. The down-regulation expressions of survivin gene, bcr/abl gene and bcr/abl -related P210 may play an important role in the apoptotic effect of Berbamine in leukemic cells. However, the effects in vivo and its mechanism remain to be identified. In this study, the effects of berbamine in nude mice bearing human leukemic cell xenografts were tested.
Methods: The nude mice (BALB/C-nu/nu) were pre-treated with X ray 400cGy/2min, then 2×107 K562 cells and Jurkat cells were subcutaneously injected into the mice respectively. Rapid growth of solid tumors was observed in nude mice. One week later, the tumor-bearing mice were randomly divided into three treatment groups: untreated controls; berbamine-treated group (a dose of 1.0mg/day × 20 day, subcutaneously injected); Ara-C-treated group(a dose of 0.8mg/day, × 7 day, subcutaneously injected). Four weeks later, all the experimental mice were euthanized.
Results: Mice that received berbamine had significantly slower tumor growth rate than did untreated mice. In K562-bearing mice, the tumor weight of berbamine-treated group was lower than that of the control group(1.46g±0.43g vs 2.90g±0.94g, P<0.01 )and the inhibition rate was 49.66%. In Jurkat-bearing mice, the tumor weight of berbamine-treated group was also lower than that of untreated group(0.96g±0.64g vs 2.28g±0.33g, P<0.01), although it was comparable to that of Ara-C-treated group(0.54g±0.38g, P=0.311). The inhibition rates were 57.89% and 76.32% respectively. Moreover, in Jurkat-bearing mice berbamine inhibited the tumor cells invasion into bone marrow. In K562-bearing mice, berbamine down-regulated the expression level of bcr/abl gene of tumor cells ((berbamine-treated group 1.07±0.05 vs untreated group 1.58±0.24, P<0.05). In addition, no harmful side effects were attributed to berbamine.
Conclusion: In vivo, berbamine could aslo take a better antileukemia effect and the dose of berbamine used was safe with almost no side effects in nude mice. Berbamine extracted from Chinese herb might be a promising candidate of new drugs for clinical anticancer treatment, especially for bcr-abl+ diseases.
Tangeretin Induces Caspase Dependent Apoptosis and G2/M Arrest in the Erythroleukemia Cell Line K562 In Vitro.
Authors: Sofie Lust , Barbara Vanhoecke , Marc Bracke , Fritz Offner 
Published: October 2019

Abstract
Introduction
Tangeretin, a polymethoxyflavon present in citrus peel oil, was found to inhibit Erk-phosphorylation in T47-D breast cancer cells, induce cell death and block invasion in the chick heart invasion assay. Erk-phosphorylation has been implicated in the growth of bcr-abl transformed cell lines as a result of constitutive abl-activation. Here we investigate whether tangeretin can induce apoptosis and growth arrest in the bcr-abl+ erytroleukemia cell line K562, how it affects signal transduction pathways and the balance between pro- and anti-apoptotic proteins.
Methods
Tangeretin was dissolved in DMSO and used at concentrations up to 100 μM. K562 cells were cultured in RPMI 1640–10% FBS in vitro. Proliferation was followed by MTT test. Apoptosis, cell cycle analysis and bcl-2 expression was assessed by flow cytometry. PARP, Erk1/2, p38, Akt, JNK, p70S6K, and P-p38, P-Akt, P-JNK, and P-p70S6K, bcl-XL and mcl-1 were assessed by Western Blot.
Results
Tangeretin shows a time and concentration dependent effect on bcr-abl + K562 cells with a LD50 of 50–70 μM. This effect is accompanied by a G2/M arrest and a significant increase in the percentage of subG0 cells and PARP cleavage at 24 hrs. In short term kinetics (30 minutes) tangeretin inhibits the phosphorylation of Erk. No effect on total Erk1/2, p38, Akt, JNK, p70S6K, and P-p38, P-Akt, P-JNK, and P-p70S6K could be observed. After 24 and 48 hours of treatment, tangeretin is capable of stimulating the phosphorylation of Erk and p70S6K. At the same time activation of procaspase-3 and -9 and downregulation of the anti-apoptotic proteins Mcl-1 and Bcl-xL were seen. Bcl-2 expression was analysed by flow cytometry and was also downregulated.
Conclusion
The citrus flavonoid tangeretin is capable of inducing apoptosis and growth arrest in bcr-abl positive K562 cells through activation of caspase-3 and -9 accompanied by a biphasic change in phosphorylation of Erk and p70S6K.