bluuebunny/crossref_metadata_2025_split huggingface dataset:
Population Based Genotyping of Human Leukocyte Antigen (HLA) in Hodgkin Lymphoma: EBV Positive HL Is Associated with HLA Class I and EBV Negative HL Is Associated with HLA Class III.
Authors: Diepstra Arjan , Niens Marijke , Vellenga Edo , te Meerman Gerard J. , Schaapveld Michael , Nolte Ilja M. , van Imhoff Gustaaf W. , Poppema Sibrand 
Published: April 2020

Abstract
An inherited susceptibility to Hodgkin Lymphoma (HL) is indicated by the variation in incidence among race/ethnicity groups, aggregation of the disease in families and by association with human leukocyte antigens (HLA). In this study we conducted a detailed screening analysis of the complete HLA region in EBV-positive and EBV-negative patients with HL.
In total, 200 patients and 348 family-based controls of the Caucasian population of the Northern Netherlands participated in this population-based study. Paraffin embedded tissue of all patients was obtained and used for revision according to the WHO classification. In addition, analysis of EBV status was performed. 54 patients were EBV-positive (33 NS, 14 MC, and 7 other classical cases) and 146 patients were EBV-negative (124 NS, 4 MC, 13 NLP, and 5 other classical cases). 33 microsatellite markers located in the HLA region 6p21 were used for genotype screening.
Allele, genotype and two-locus haplotype association analyses were used to search for differences between EBV-positive and negative patients and family controls using a t-test to assess significance. In the EBV-positive patient group, HL was associated with an allele of 126 bp for D6S265 and an allele of 284 bp for D6S510 (p=0.00031). These markers are located in the HLA class I subregion. Individuals homozygous for 126 allele of D6S265 were observed in 34.4% of the EBV-positive patient group and 5.2% of controls (odds ratio (OR)= 6.6). The odds ratio for individuals heterozygous for 126 allele of D6S265 was lower (OR= 2.5).
In addition, Haplotype Sharing Statistics (HSS) was used to search for differences in haplotype sharing between patients and family controls. The HSS assumes that haplotype segments of patients from a founder population are conserved in the region spanning a disease locus.
The HSS analysis showed strongest haplotype sharing around marker D6S273 in patients compared to controls (p&lt;0.0001). The sharing was less evident in the EBV-positive subgroup compared to the EBV-negative subgroup, possibly due to low power. D6S273 is located at the telomeric end of the HLA class III region nearby TNF-alpha, TNF-beta and heat shock protein genes. Our results indicate that part of the HLA class I and part of the HLA class III region are associated with susceptibility to classical HL, with the HLA class I association being specific for EBV positive HL. We will further analyze both regions aiming to find genes and polymorphisms associated with the development of HL.
Mutations of the PTPN11 Gene in Childhood Hematological Malignancies.
Authors: Chen Yuyan , Takita Junko , Hiwatari Mitsuteru , Hanada Ryoji , Kikuchi Akira , Tsuchida Masahiro , Sugita Kenichi , Sako Masahiro , Taki Tomohiko , Ogasawara Mizuho , Hayashi Yasuhide 
Published: April 2020

Abstract
The PTPN11 gene encodes SHP2, which is a protein tyrosine phosphatase functioning as signal transducer downstream to growth factors and cytokine receptors and its function is mediated, at least in part, through the Ras/Raf/ERK cascade in hematopoietic and non-hematopoietic cells. Recently, it has been reported that germline mutations in PTPN11 cause Noonan syndrome and a gain-of-function somatic mutations in PTPN11 has also been reported in juvenile myelomonocytic leukemia (JMML). To investigate the prevalence of mutations in PTPN11 in childhood acute myeloid leukemia (AML) and acute lymphoblastic leukemia (ALL), we screened the hot spot of PTPN11, exon 3, in 80 cell lines, including 14 AML, 5 chronic myeloid leukemia, 14 T-cell ALL and 47 B-precursor ALL cell lines, and 207 fresh samples, including 20 myelodysplastic syndrome (MDS), 3 JMML, 85 AML, 57 B-precursor ALL patients as well as 42 infant leukemia patients (6 AMLs, 35 ALLs, 1 mixed lineage leukemia), using polymerase chain reaction-single strand conformation polymorphism and direct sequencing analyses. In exon 3, mutations were observed in 2 of 14 (14.3%) AML cell lines (Asp61Val and Glu76Gly). A missense mutation (Ala72Val) was detected in 1 of 85 (1.2%) AML patients (a 9-year-old girl with FAB-M0). In 20 MDSs, a missense mutation (Asp61Val) (5%) was identified in a RAEB-T patient. In 3 JMMLs, 2 missense mutations (66.7%) were detected; one was Gly60Ala, and the other was Glu76Val. In 42 infant leukemia patients, we detected only one missense mutation (Ala72Asp) (2.4%) in an AML-M5b patient. However, we did not detect any mutations of exon 3 in 61 ALL cell lines and 92 ALL patients including 35 infant ALL patients. The screening for other coding regions is still undergoing although more than 90% of the reported mutations were clustered in exon 3. In conclusion, our data suggest that the PTPN11 mutations are involved in myeloid hematological malignancies rather than ALL.
Expression of Cyclooxygenase-2 (COX-2) in Human Leukemias and Hematopoietic Cells.
Authors: Lilly Michael B. , Drapiza Leslie , Sheth Milan , Zemskova Marina , Bashkirova Svetlana , Morris Joan 
Published: April 2020

Abstract
COX-2 has been implicated in the development of many epithelial cancers, as well as in tumor angiogenesis. COX-2 inhibitors have been shown to have anti-tumor activity in experimental cancer. Little information exists, however, on the expression or role of COX-2 in hematologic malignancies. We have use a variety of immunochemical assays to document expression of COX-2 in human and murine leukemias and hematopoietic cells. The factor-dependent murine cell lines FDCP1 and 32D expressed COX-2 when growing continuously in the presence of IL-3; expression declined markedly when growth factor was removed. FDCP1 cells constitutively expressing bcl-2, pim-1, or bcr-abl had markedly elevated levels of COX-2, and continued to express this enzyme even after removal of growth factor. To assess COX-2 expression in human hematopoietic cells we developed a flow cytometry assay using a FITC-labelled anti-COX-2 MoAb (Cayman). Cells were washed once in serum-free medium, fixed briefly in 1% paraformaldehyde, permeabilized with PBS/0.2% Triton X100, then stained with antibody. Negative control samples were processed similarly but stained with antibody that had been preincubated with immunizing peptide. Specific COX-2 staining was interpreted as the difference between the histograms from blocked versus unblocked anti-COX-2 antibody, as determined by Kolmogorov-Smirnoff analysis. In buffy coat preparations from normal donors, we found constitutive expression of COX-2 in lymphocytes (both B-cells and T-cells). In contrast little or no COX-2 was detected in unstimulated neutrophils or monocytes. In human acute myelogenous leukemia (AML) cell lines we found COX-2 expression to be universal and easily detected. In several cell lines we confirmed the results of our flow cytometry assay with immunoblotting. We further examined 25 cryopreserved samples of human acute leukemia blasts obtained from peripheral blood. COX-2 expression was variable, but universal. Levels generally were less than those seen in immortalized cell lines, and did not correlate with blasts morphology (AML, ALL, APL, AMoL, CML-BT). To determine if COX-2 inhibitors could play a role in the treatment of acute leukemias, we performed cytotoxicity assays using the COX-2 specific inhibitors, celecoxib and NS398. Survival and growth of human AML cell lines were inhibited by both agents. These data demonstrate that 1) a variety of oncogenes can induce expression of COX-2 in hematopoietic cells, 2) clinical human acute leukemias uniformly express COX-2 in circulating blasts, and 3) COX-2 inhibitors are cytotoxic for human leukemia cells. Combination therapies for acute leukemias may evaluate the incorporation of COX-2 inhibitors for added cytotoxic effects or angiogenesis inhibition.
Characterization of Secondary Alterations in Mantle Cell Lymphomas Using Matrix-/Array CGH.
Authors: Steinemann Doris , Tauscher Marcel , Rudolph Cornelia , Emura Makito , Abe M. , Daibata M. , Matsuo Yoshinobu , Drexler Hans G. , Radlwimmer Bernhard , Kestler Hans A. , Lichter Peter , Schlegelberger Brigitte 
Published: April 2020

Abstract
Overexpression of Cyclin D1 due to the chromosomal translocation t(11;14)(q13;q32) alone is not sufficient to induce the development of mantle cell lymphoma (MCL). Therefore, secondary genetic alterations seem to be necessary for the malignant transformation and may determine the clinical course of the disease. In order to define chromosomal imbalances more precisely, we analyzed six t(11;14)-positive mantle cell lymphoma cell lines (Granta-519, NCEB1, JeKo-1, Rec-1, SP-53 and HBL-2) by means of matrix-/array-based comparative genomic hybridization (array-CGH), a new molecular tool that allows the genome-wide screening of chromosomal imbalances. The microarray used contains 6251 individual BAC/PAC clones. Clones were selected to reach a genome-wide resolution of 1 Mb and an even higher resolution of up to 100kb in recurrently aberrant regions of MCL. In addition, regions containing known tumor suppressor genes and oncogenes were covered by a high density of clones. The hybridization of tumor DNA against normal control DNA and the subsequent washing steps were carried out using the automated slide processor Lucidea (Amersham-Pharmacia Biotech). Based on the normalized fluorescence ratios computed as log2 values, we were able to detect amplifications as well as single gains and losses. The most frequent alterations were losses in 9p21.3, 2p11.2, 22q11.22, 1p21.1-p31.2, 13q14, 11q22, 6q21, 6q27, 17p13 and gains in 7p14.1, 7q11.2, 2q37.1, 8q24, 12q13 and 18q21. These results are in agreement with the recently published data from deLeeuw et al. (HMG Advance Access June 30, 2004). Up to now, losses of 2p11.22 (all cell lines except for JeKo-1) and 22q11.22 (all cell lines except for Rec-1) have not been known as recurrent aberrations of MCL. Selected chromosomal losses (p16, p53) and the amplification of BCL2 in Granta-519 were confirmed by means of fluorescence in situ hybridization using commercially available probes (Abbott Diagnostics, Wiesbaden, Germany). Matrix-/array CGH analyses enabled us to further delineate important regions of gain and loss like 13q14. In conclusion, the cell lines are excellent model systems which will facilitate the identification and characterization of novel genes which play important roles in the pathobiology of MCL.
Rare Mutations of the PIK3CA Gene in Hematologic Malignancies.
Authors: Muller Claudia I. , Miller Carl W. , Hofmann Wolf-K. , Kawamata Norihiko , Koeffler H. Phillip 
Published: April 2020

Abstract
Phosphatidylinositol 3-kinase (PI3K) is a lipid kinase that is activated in advanced cancers through inactivation of the PTEN tumor suppressor gene. Somatic mutations in the p110-alpha catalytic subunit, PIK3CA occur in colon, gastric, breast and lung cancers as well as in glioblastomas and colorectal adenomas. Mutations were found in two “hot spots”: the helical (exon 9) and kinase (exon 20) domains. Mutational analysis of PIK3CA in hematologic malignancies has not been reported. We performed a screening analysis of 28 cell lines from human hematologic malignancies as well as 46 AML and MDS samples and 42 lymphoma samples by polymerase chain reaction - single strand conformation polymorphism (PCR-SSCP) and nucleotide sequencing of the two “hot spots”. Two colon adenocarcinoma cell lines (SKCol1, SW403) were used as positive controls and revealed the known missense mutation (Q546K) in exon 9. A novel missense mutation occurred in the erythroid chronic myeloid leukemia cell line K562, causing an amino acid change from Glutamic acid to Alanine at amino acid position 545 of exon 9 (E545A). In the kinase domain (exon 20), a novel polymorphism was observed in two different MDS patients at Threonine residue 1025. Experiments are exploring the functional importance of the PIK3CA mutation and the PIK3CA polymorphism in exon 20. In summary, PIK3CA mutations are infrequent in hematologic malignancies.
Identification of Target Genes for the Tumor Suppressor RIZ1 Using Gene Expression Profiling.
Authors: Dong Wei-Feng , Takahashi Naoto , Bainbridge Matthew N. , Hull Andrea R. , Scott Stuart A. , Geyer C. R. , DeCoteau John F. 
Published: April 2020

Abstract
RIZ1 (PRDM2) is a tumor suppressor gene on 1p36 that frequently undergoes deletion, rearrangements, and loss of heterozygosity in a broad spectrum of tumors. RIZ1 is a member of the nuclear protein methyltransferase superfamily involved in chromatin remodeling. RIZ1 contains a ~130 amino acid conserved domain (PR or SET) that is important in chromatin-mediated regulation of gene expression and in the development of cancer. RIZ1 methylates Histone H3 on K9 and this activity may play a role in transcription repression as H3-K9 methylation is known to be associated with repression. Aberrant activities or mistargeting of chromatin modifying activities are proving to have unexpected links to cancer. We and others have shown that RIZ1 expression is down regulated in human leukemias and in the human erythroleukemia cell line K562. Expression of RIZ1 in K562 reduced proliferation, increased apoptosis, and promoted erythroid differentiation. To understand how RIZ1’s DNA binding, methyltransferase, and transcription repressor functions are related to its tumor suppressor activity it is necessary to characterize RIZ1 target genes. We used DNA microarrays to globally monitor how RIZ1 affects gene expression profiles. We constructed a K562 cell line with RIZ1 stably integrated under the control of a CMV promoter and analyzed the gene expression profiles of K652 and K562 + RIZ1 using a 42K Stanford human gene microarray. By comparing the gene expression profiles of these cell lines, we identified potential RIZ1 gene targets that are up and down regulated in the presence of RIZ1. In total, we identified 5 upregulated genes and 20 down regulated genes using significance analysis of microarrays (SAM) and standard deviation filter analysis of the gene expression data. RIZ1-mediated changes in gene expression profiling indicate that RIZ1 is potentially involved in the regulation and connection of the IGF-1 (IGF-1, IGFBP2) and integrin (LMS1) pathways, and in the activation of the TGF-β (SPARC) pathway. The genes perturbed by RIZ1 expression suggest that the tumor suppressor properties of RIZ1 arise from its control of proliferation, apoptosis and differentiation using these pathways. Finally, we observed an overrepresentation of the SP-1 transcription factor binding sites in genes that are upregulated in the absence of RIZ1. This correlates with the ability of RIZ1 to recognize SP1 sequences.
Effect of Dioxin on Normal Human Hematopoietic and Leukemic Cells.
Authors: Deliliers Giorgio Lambertenghi , Fracchiolla Nicola S. , Servida Federica , Bosari Silvano , Soligo Davide 
Published: April 2020

Abstract
2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) is the prototypical agonist of the aryl hydrocarbon receptor (AhR), a member of the erb-A family that also includes receptors for steroids, thyroid hormones, peroxisome proliferators and retinoids. When bound to dioxin, the AhR can bind to DNA and alter the expression of various genes, including cytokines and growth factors. TCDD has a large number of biological effects, such as long-lasting skin disease, cardiovascular disease, diabete and cancer. An increase risk of Hodgkin’s disease, non-Hodgkin’s lymphoma and myeloid leukemia was observed after 15 years in the population exposed to dioxin following the 1976 accident in Seveso, Italy. In this study, we analysed the effect of escalating doses of TCDD on the human myeloid leukemic cell lines HL60 (promyelocytic leukemia) and K562 (chronic myelogenous leukemia), as well as on human CD34+ progenitor cells from the leukapheresis of normal donors stimulated with G-CSF. The possible specific modulation of gene expression induced by TCDD was then tested by means of macroarray analyses (Clontech), the results of which were successfully validated by real-time quantitative PCR on five candidate genes. The dioxin dose capable of inhibiting the growth of 50% of the colonies in semisolid medium (IC50 calculated using the CalcuSyn computer program) was 33 nM for HL60, 28 nM for K562, and 20 nM for the CD34+ cells. The HL60, K562 and CD34+ cells tested before and after exposure to 20 nM of TCDD allowed us to identify a series of modulated genes. The up-regulated genes included LUCA15 putative tumour suppressor, cyclin-D binding Myb-like protein (hDMP1), MAPK/ERK kinase 6, ras-related protein RAB2, RalB GTP-binding protein, transcription factor ZFM1, and BRCA1-associated ring domain protein (BARD1). The down-regulated genes included found c-myc, TNF alpha precursor, ICAM1, MIP1-beta, interferon gamma-induced protein precursor (gamma-IP10), granulocyte-macrophage colony stimulating factor (GM-CSF), monocyte chemotactic protein 1 precursor (MCP1). All of these genes are variously involved in the processes of proliferation, differentiation and transformation in hematological and tumoral cell models. On the basis of these data, we can hypothesise that the inhibition of clonogenic potential and the gene expression induced by TCDD exposure on normal CD34+ progenitor cells plays a role in the neoplastic transformation of hemopoietic stem cells. This supports the epidemiological data indicating an increased hematological cancer risk in the population accidentally exposed to TCDD.
Proteinated Elemental Selenium Potentiates Anti-Tumor Effect of Ionizing Radiation and Chemotherapeutic Agents but Is Only Minimally Affected by Drug Resistance Mechanisms.
Authors: Tsujino Ichiro , Miyagi Kiyoko , Sampson Reynee W. , Gunther Wolfgang H.H. , Krieg Marianne , Sieber Fritz 
Published: April 2020

Abstract
Elemental selenium generated by the photobleaching of selone photosensitizers combined with serum albumin and lipoproteins to generate conjugates that were highly cytotoxic to leukemia and selected solid tumor cells but well tolerated by normal CD34-positive hematopoietic cells. Selenium-protein conjugates were internalized by an endocytotic mechanism and localized in lysosomes. Internalized conjugates caused an extremely rapid and extensive (up to 80% in 1 hour) depletion of intracellular glutathione (GSH), the oxidation of 2′,7′-dichlorofluorescin, a loss of plasma membrane asymmetry, a breakdown of mitochondrial potential, and the activation of several caspases. Additive or synergistic anti-tumor effects were obtained when Se-protein conjugates were used in combination with ionizing radiation, melphalan, amifostine, 4-hydroperoxycyclophosphamide, edelfosine, buthionine sulfoximine, or moderate doses of arsenic (III) oxide. For example, pretreatment with a nontoxic dose of amifostine enhanced the depletion of L1210 leukemia cells from 7 log to 12 log (depletions in excess of 6 log estimated from linear extrapolations of survival curves) while the yield of normal CD34-positive cells remained at 100%. Antagonistic interactions were obtained with simultaneously applied cisplatin or very high doses of arsenic (III) oxide. The antagonistic interaction with cisplatin probably reflected a competition of cisplatin and selenium for the same binding site at or near cysteine-34 of albumin. Melphalan-resistant L1210/L-PAM1 leukemia cells (elevated intracellular GSH) were more sensitive to Se-protein conjugates than wild-type cells because of an unexpected increase in conjugate uptake by mutant cells. Cisplatin-resistant H69/CDDP cells (elevated GSH, metallothioneine, glutathione-S-transferase-pi) were slightly more sensitive than wild-type cells. Cisplatin-resistant PC14/CDDP cells (reduced drug uptake) and adriamycin-resistant HL-60/ADR cells (MRP-mediated efflux) were slightly less sensitive than the corresponding wild-type cells. In the latter cases, the reduced sensitivity of mutant tumor cells correlated with reduced conjugate uptake and/or higher intracellular GSH levels. Taken together, the above results suggest that compounds modeled after our Se-protein conjugates may prove useful for the systemic therapy of leukemia and selected solid tumors. Supported by CA77387, MACC Fund, Children’s Hospital Foundation, and Wisconsin Breast Cancer Showhouse for a Cure.
Blockade of Highly Expressed CD55 Related to Tumor Bulkiness by RNA Interference Overcomes Resistance to CDC with Rituximab.
Authors: Terui Yasuhito , Sakurai Takuma , Mishima Yuko , Mishima Yuji , Yokoyama Masahiro , Takahashi Shunji , Itoh Yoshinori , Hatake Kiyohiko 
Published: April 2020

Abstract
[Background] Recently, We have presented that sensitivity to anti-CD20 antibody-mediated CDC was different during cell growth dependent on expression of CD55 (ASH 2003, San Diego). In some cases with malignant lymphoma after the treatment of anti-CD20 antibody, lymphoma cells get resistance to the treatment of anti-CD20 antibody. Moreover, bulky disease of malignant lymphoma like 7.0 cm of tumor gets resistance to rituximab. One of some regulators in complement system, CD55, is a major regulator of the alternative and classical pathways of complement activation and is expressed on all serum-exposed cells. Here, we have found the relationship among extirpated lymph nodes, sensitivity to CDC, and CD55 expression, and small interference of RNA (siRNA) for CD55 is a useful tool for blockade of CD55 in monoclonal antibody therapy.
[Methods] Human B cell line, Daudi and Rajii cells were used as sensitive and insensitive controls in complement-mediated cytotoxycity (CDC) with anti-CD20 antibody. Lymphoma cells were collected from extirpated lymph nodes of the patients with lymphoma. CDC assay with anti-CD20 antibody was performed with FACscan or under confocal laser scanning microscopy system. Three parts of siRNAs for CD55 (CD55-N, -M, and -C) were designed, and transfected to the cells using lipofectin
[Results] The relationship between sensitivity to CDC and size of extirpated tumor showed negative correlation. The formula’s intercept was 7.775 cm, suggesting that lymphoma with more than 7 cm of size is not effective in rituximab therapy as Coiffier’s report. The level of CD55 expression on lymphoma cells was correlated with size of its lymph node, and in some patient with lymphoma, level of CD55 expression on Lymphoma cells and susceptibility to CDC were different among before, after relapse and after partial remission, indicating that susceptibility to CDC depends on CD55 expression. This suggests that increased cell numbers contribute to higher or enhanced CD55 expression and resistance to CDC with rituximab. Lymphoma cells from all five cases with recurrent lymphomas strongly expressed CD55 molecules under laser scanning confocal microscopy. Percentages of dead cells showed no significant differences among transfection with and without CD55-N, CD55-M and CD55-C before CDC assay. Percentage of PI-positive cells in transfection with CD55-N significantly increased from 7.1% to 67.9%. These indicate that the siRNA against CD55 (1–380 nucleotides), CD55-N could efficiently knock down the expression of CD55 on freshly isolated lymphoma cells from recurrent lymphomas, and that it could induce cell death in freshly isolated lymphoma cells from recurrent lymphomas by CDC.
[Conclusion] This siRNA for CD55 could be a good tool for blockade of CD55 in resistance and bulkiness related with highly expressed CD55 with monoclonal antibody therapy.