bluuebunny/crossref_metadata_2025_split huggingface dataset:
C/EBPδ Modulates Cell Growth, Differentiation and Apoptosis of Myeloid Leukemia, Prostate and Breast Cancer Cells.
Authors: Gery Sigal , Stanosaki Sakae , Ikezoe Takayuki , Hofmann Wolf K. , Gombart Adrian F. , Koeffler H. Phillip 
Published: October 2019

Abstract
C/EBPδ belongs to the family of highly conserved CCAAT/enhancer binding protein (C/EBP) transcription factors. Members of this family play a critical role in the regulation of mitotic growth arrest and differentiation in numerous cell types. To examine the consequences of C/EPBδ expression, we transfected C/EPBδ into CML myeloid leukemia (KCL22, K562), prostate (LNCaP, PC3, DU145), and breast (MCF-7, T47D, MDA-MB-231) cancer cell lines. C/EBPδ expression resulted in a proliferative arrest and an increase in apoptosis of the myeloid leukemia cells, as well as the prostate cells LNCaP and PC3, and the breast cells MCF-7 and T47D. In contrast, DU145 prostate and MDA-MB-231 breast cancer cells were not inhibited by C/EBPδ, indicating that the biologically properties of C/EBPδ depend upon its cellular context. We further studied the molecular mechanisms underlying the affect of C/EPBδ expression in CML leukemic cells. Myeloid differentiation of KCL22 and K562 blast cells as shown by morphologic changes and induction of secondary specific granule genes, occurred within 4 days of inducing expression of C/EBPδ. Furthermore, expression of C/EBPδ was associated with downregulation of c-Myc and cyclin E, and upregulation of the forkhead transcription factor FoxO1a (FKHR) and the cyclin-dependent kinase inhibitor p27Kip1. In addition, microarray analysis showed that C/EBPδ mRNA is upregulated during granulocytic differentiation of normal CD34+ bone marrow cells, suggesting that C/EBPδ is involved in lineage-specific differentiation. Taken together, these results show that expression of C/EBPδ in BCR-ABL-positive CML cells in blast crisis, is sufficient for neutrophil differentiation and suggest that ectopic induction of C/EBPδ in the blastic phase of CML, as well as in certain cases of prostate and breast cancers, may hold promising therapeutic potential.
Genetic Identification of Hematopoietic Stem Cell Immortalization Genes.
Authors: Du Yang , Jenkins Nancy A. , Copeland Neal G. 
Published: October 2019

Abstract
Hematopoietic cancer is thought to arise from small populations of immortalized cancer stem cells that give rise to phenotypically diverse cells with less proliferative capacity. Cancer stem cell immortalization genes represent attractive drug targets for treating human cancer. We have found that immortalized cell lines can be generated in vitro following infection of mouse bone marrow cells with replication defective murine stem cell virus (MSCV). Immortalized myeloid progenitors can be selected in the presence of SCF plus IL-3 while immortalized multi-potent early hematopoietic progenitor cells can be selected with SCF and Flt3 ligand. So far, more than 80 such lines have been generated and they exhibit many properties attributed to cancer stem cells; they undergo unlimited self-renewal yet are able to give rise to phenotypically diverse cells with less proliferative capacity and in some cases they are leukemogenic in transplanted hosts. Immortalization often results from the insertional mutagenesis of human leukemia gene orthologues or genes that regulate them. Insertional mutagenesis by MSCV thus produces cells that share many properties attributed to cancer stem cells and may mark a subset of genes important for the immortalization of leukemic stem cells.
Cyclin-C: Analysis of a Candidate Tumour Suppressor Genes on 6q15-q21 in Malignant Lymphoid Cell Lines and Lymphoid Acute Leukemias.
Authors: Sinclair Paul B. , Mitchell Wayne , Kaeda Jaspal , Foroni Letizia 
Published: October 2019

Abstract
Using FISH and LOH in ALL cases with microscopically visible deletions of the long arm of chromosome 6q, we previously defined a region of minimal deletion (RMD) in a spectrum of lymphoid malignancies and with other investigators have suggested that the region may harbour several tumour suppressor genes. (Sinclair et al 2004; Cancer Research, 64: 4089). 15 recognised genes were positioned in the RMD and three were found expressed in bone marrow: GRIK2, C6orf111 and Cyclin-C, the investigation of which is reported in this study.
GRIK2 analysis. Combining published RMD in ALL with our own data, we extensively analysed GRIK2 in ALL patients carrying heterozygous 6q deletion. Although a paternally inherited non-silent mutation of GRIK2 was identified in one of 14 patients, we concluded that loss of one or more other genes in the 6q15-q21 region was likely to contribute to ALL pathogenesis.
Cyclin-C (CCNC) analysis. Lymphoid cell lines without and with del (6q)(Peer, Molt-4 and NKL) were assessed for expression levels of C6orf111 and Cyclin-C and other candidate tumour suppressor genes within the region (FLASH, Q9NR58, Cx43, BACH2, BLIMP1, APG5L, TAK1 and AIM1) using real-time quantitative RT-PCR (RQ-PCR). While easily detectable in all other cell lines, no expression of CCNC was demonstrated in NKL (by RT-PCR and Western blotting), this in spite of the presence of at least one copy of the gene (as demonstrated by FISH using PAC P13743 which contains CCNC) suggesting that expression of the second allele was ablated through either micro-deletion, point mutation or epigenetic silencing. Expression levels of other candidate genes were similar, albeit with minor variations, in all cell lines. We further analysed expression of CCNC in whole PB and BM, a variety of haemopoietic cells isolated from PB and in 66 de novo ALL patients (9 T ALL; 48 B cell ALL (predominantly common ALL) and 9 other ALL). Expression was relatively high in all cell lines, intermediate in normal T-lymphocytes and low in other normal cells. Leukemic cells collected from diagnostic material from adult acute lymphoid malignancies showed a wide variation in levels of CCNC expression. To exclude the possibility that low expression in some cases may be due to the presence of a high proportion of normal cells CCNC levels were normalised against Ki67 expression (as an indicator of mitotic index) by RQ-PCR. At least 27 patients showed a CCNC level below the median value. Twenty-five cases showed value above the median value. Levels of expression of CCNC and Ki67 were correlated with survival, immunophenotype or other clinical parameters, but no statistically significant correlation was demonstrated.
Disparate Mechanisms of Antifolate Resistance Provoked by Methotrexate and Its Metabolite 7-Hydroxymethotrexate in Leukemia Cells: Implications for Efficacy of Methotrexate Therapy.
Authors: Albertioni Freidoun , Jansen Gerrit , Fotoohi Kambiz , Assaraf Yehuda G. , Rothem Lilah , Stark Michal , Kathmann Letje , Gregorczyk Jacek , Peters Godefridus J. 
Published: October 2019

Abstract
Methotrexate (MTX) is one of the leading drugs in the treatment of leukemia, but extensive metabolism to 7-hydroxymethotrexate (7-OHMTX) can limit its therapeutic efficacy. In this study we investigated whether 7-OHMTX itself can provoke antifolate resistance that may further disrupt MTX efficacy. For this purpose we developed resistance to 7-OHMTX as well as MTX in two human leukemia cell lines (CCRF-CEM and MOLT-4) by stepwise exposure to increasing concentrations of 7-OHMTX and MTX. Consequently, both leukemia cell lines displayed marked levels of resistance to 7-OHMTX (>10 fold) and MTX (>75 fold), respectively. The underlying mechanism of resistance in the MTX-exposed cells was a marked decrease (>10-fold) in reduced folate carrier (RFC)-mediated cellular uptake of MTX. This was associated with transcriptional silencing of the RFC gene in MTX-resistant CCRF-CEM cells. In contrast, the molecular basis for the resistance to 7-OHMTX was solely due to a marked decreased (> 95%) in folylpolyglutamate synthetase (FPGS) activity which conferred >100-fold MTX resistance upon a short term exposure to this drug. This is the first demonstration that 7-OHMTX can provoke distinct modalities of antifolate resistance as compared to the parent drug MTX.
Src Homology 2 Domain Binding as a Phosphoproteomic Approach to Signaling in Acute Lymphoblastic Leukemia.
Authors: Horstmann Martin A. , Nollau Peter 
Published: October 2019

Abstract
A general theme of orchestrated signal transduction is played by activated receptor phosphotyrosine kinases (PTK) and receptor PTK targets which propagate signals via recognition of sequence-specific phoshorylated tyrosines by so-called Src homology 2 (SH2) domains. SH2 domain interactions are used as a means of recruiting target proteins to activated PTKs and to translocate them to the plasma membrane where many effector proteins activated by receptor PTKs such as phospholipase C-γ or PI-3 kinase have their substrates. SH2 domains make up the most prevalent type of phosphotyrosine binding domains involved in signaling downstream of activated PTKs. SH2 domains are not only present in proteins with intrinsic enzymatic activity but also in adaptor proteins which shuttle effector enzymes to target signaling complexes. Increasing numbers of diseases are known to involve phosphotyrosine specific kinases and/or phosphatases going awry exemplified by the notorious ErbB2 receptor PTK in breast cancer or the Bcr-Abl PTK in CML. Currently, the tyrosine phosphorylation state in most acute lymphoblastic leukemias is undefined which is predicted to differ among the various subgroups and to be distinct from the signaling state of normal hematopoietic cells. To identify aberrant tyrosine kinase or phosphatase activity in the various types of acute lymphoblastic leukemia is of great interest since enzymes in general make good targets for drugs. A novel SH2 domain binding approach is presented which can detect distinctive profiles of tyrosine-phosphorylated proteins in complex mixtures of cellular proteins. A battery of SH2 domains is employed as probes in a competitive far-Western blot based assay to identify specific tyrosine-phosphorylated sites which reflect active signaling pathways in a cell. A further refinement of this technology is under way with DNA-tagged probes being developed which allow for multiplexing and high throughput quantitative assessment of SH2-domain binding by quantitative PCR or microarray technologies.
Murine Melanomas Expressing High Levels of SDF-1 Repel and Escape Control by Tumor Specific T-Cells.
Authors: Vianello Fabrizio , Papeta Natalia , Kircher Moritz F. , Toner Mehmet , Weissleder Ralph , Irimia Daniel , Poznansky Mark C. 
Published: October 2019

Abstract
Most antigenic tumors are able to evade the immune system despite T cell recognition of tumor specific antigens. The chemokine, stromal derived factor- 1 (SDF-1 or CXCL12) is constitutively expressed by both normal and neoplastic tissues and is involved in tumor growth, metastasis and modulation of the anti-tumor immune response. We have previously shown that human T cells are repelled by the chemokine SDF-1, in a concentration-dependent and CXCR4 receptor-mediated manner. We proposed that the repulsion of tumor-specific T cells from a tumor expressing SDF-1 may represent a novel mechanism of immune evasion. B16 melanoma cells stably expressing OVA were genetically modified to constitutively express SDF-1 using a bicistronic MSCV2.2 retroviral transfer vector encoding murine SDF-1α and EGFP. SDF-1 generated by transduced cells was 58 ± 28.5 ng/ml/1x106 cells/24 hours as measured by ELISA. Immunization of mice with irradiated B16/OVA cells lead to destruction of B16/OVA.MSCV control tumors but not tumors expressing high levels of SDF-1 (p=0.0001). Failure to reject B16/OVA.SDF-1 tumors was associated with a reduction of T cell infiltration compared to control B16/OVA.MSCV (p=0.001). Similarly, early recruitment of adoptively-transferred OVA-specific CD8+ T cells into B16/OVA.SDF-1 tumors was significantly reduced in comparison to B16/OVA.MSCV control tumors as demonstrated by immunohistochemistry and real-time magnetic resonance imaging of nanoparticle labeled CTLs (p=0.018). Transferred memory OVA-specific CD8+ T-cells demonstrated antitumor activity against B16/OVA.MSCV control tumors but not against B16/OVA-SDF-1 tumors (p=0.04). Isolation and FACS analysis of tumor-infiltrating lymphocytes showed a 4-fold reduction of T cells in B16/OVA.SDF-1 compared to B16/OVA.MSCV control tumors (p=0.005). The in-vitro killing activity of tumor specific CD8+ T cells against B16/OVA.SDF-1 tumors was significantly reduced compared to B16/OVA.MSCV control tumors when measured in 51Cr release assay performed in a flat-bottom well system where cytotoxicity was dependent on effector cell migration (p=0.0004). Preincubation of OT-I CD8+ T cells with the CXCR4 antagonist AMD3100 restored their cytolytic activity against B16/OVA.SDF-1 cells (p=0.045). These data support the thesis that the active movement of tumor-specific T cells away from SDF-1, termed fugetaxis, may provide a novel mechanism by which a tumor evades challenge by immune effector cells and raises the possibility of the development of a novel immunotherapeutic approach to cancer.
Flow Cytometric Expression of bcl-2 by CD10+ B-Cells Reliably Distinguishes Follicular Lymphoma from Follicular Hyperplasia.
Authors: Kaleem Zahid , Leonard Ronald L. 
Published: October 2019

Abstract
The diagnosis of follicular lymphoma (FL) is often straightforward in most biopsy specimens. In a minority of cases, however, a differentiation from follicular hyperplasia (FH) can be challenging, especially in small needle core biopsies. The difficulty can be compounded in cases of FL with non-diagnostic immunoglobulin light chain ratios and cases of lymphoma without any significant surface expression of either immunoglobulin kappa or lambda light chain. The expression of bcl-2 by follicle center B-cells is often used to distinguish FL from FH using immunohistochemistry. The interpretation of bcl-2 expression patterns by immunohistochemistry, however, can be difficult because of normal expression of bcl-2 by T-cells present in reactive lymphoid follicles and by normal expression of bcl-2 by mantle zone B-cells. We have utilized multiparameter flow cytometry to evaluate the expression of bcl-2 in cases of FL and FH with successful results. This study includes consecutive biopsy specimens from well-documented cases of FL (n = 12) and FH (n = 16). Other lymphoma types were not included. Cytoplasmic expression of bcl-2 was evaluated on CD10+CD19+ B-cells using permeabilization techniques on a four-color Beckman-Coulter Epics-XL flow cytometer. Appropriate controls were run in each case. All cases of CD10-expressing FL showed significant expression of bcl-2 by CD10+ B-cells in contrast to no significant expression of bcl-2 by CD10+ follicle center B-cells of reactive follicles (Positive predictive value, 100%; Negative predictive value, 100%). Although our patient population is small, the results indicate that the expression of cytoplasmic bcl-2 on CD10+ B-cells by flow cytometry reliably distingushes FL from FH using CD10 gating. This method is superior to immunohistochemical evaluation of bcl-2 in cases with CD10 expression. A minority of FL, however, do not show bcl-2 expression (not seen in our series) and such cases must be taken into consideration when evaluating a clonal B-cell population with CD10 but no bcl-2 expression.
DIAGNOSIS CD45+CD19+(%) CD45+CD19+CD10+(%) bcl2+(%) in CD10+ gate FL grade 1/3 65 65 38 FL grade 1/3 68 44 67 FL grade 1/3 72 72 99 FL grade 1/3 88 62 99 FL grade 2/3 72 68 99 FL grade 1/3 59 59 95 FL grade 1/3 96 84 94 FL grade 1/3 59 59 95 FL grade 1/3 45 38 99 FL grade 2/3 76 74 76 FL grade 1/3 54 47 90 FL grade 2/3 35 34 98
A Population-Based Nested Case-Control Study of Prediagnostic Serum Antibodies to JC Virus and BK Virus and Risk of Non-Hodgkin’S Lymphoma.
Authors: Rollison Dana E. , Halsey Neal A. , Shah Keerti V. , Vascidi Raphael P. , Helzlsouer Kathy J. 
Published: October 2019

Abstract
Viral infections such as HIV, EBV, and HCV have been associated with increased risk of non-Hodgkin’s lymphoma (NHL). We conducted a nested case-control study to investigate the association between prediagnostic serum antibodies to JC virus (JCV) and BK virus (BKV) and subsequent risk of NHL.
Methods: Two research serum banks were established in Washington County, MD, with more than 45,000 volunteers contributing blood samples collected in 1974 and 1989. Incident cases of NHL diagnosed through 2002 (n=170) were identified among participants by linkage to population-based cancer registries. Two controls were matched to each case (n=340) on age, sex, and date of blood draw. Pre-diagnostic circulating IgG antibodies to JCV and BKV were measured using virus-like particle (VLP) enzyme-linked immunosorbant assays (ELISA). Associations between JCV and BKV antibody seropositivity and NHL were estimated using conditional logistic regression.
Results: Overall, neither serum antibodies to JCV (odds ratio (OR) = 0.83, 95% confidence interval (CI) = 0.56–1.23) or BKV (OR = 0.98, 95% CI = 0.64–1.48) were associated with an increased risk of NHL. Results were similar across NHL subtypes. Examining time to diagnosis suggested a possible increase in NHL risk associated with JCV antibodies, but not BKV antibodies, among individuals diagnosed 12–20 years after the time of blood draw. Among a subset of individuals who donated blood in both 1974 and 1989, those who experienced an increase in JCV antibody levels over time were more than four times as likely to develop NHL as compared to those whose antibody levels steeply declined (OR = 4.59, 95% CI = 1.30–16.25).
Conclusion: The finding of increased risk with increasing JCV antibody titers suggests a possible association between reactivation of JCV infection and subsequent NHL.
High Efficacy and Good Tolerability with Rituximab In Vivo Purging Followed by High Dose Chemotheraphy and Autologous Peripheral Blood Stem Cell Transplantation (APBSCT) in Non-Hodgkin’s Lymphoma (NHL).
Authors: Shi Yuankai , Yang Sheng , Han Xiaohong , Liu Peng , He Xiaohui , Ma Jun , Ren Hanyun , Cen Xi’nan , Zhou Shuyuan , Wang Chun 
Published: October 2019

Abstract
Purpose: High-dose chemotherapy (HDC) supported by APBSCT has been shown to be superior to standard therapy in NHL. However, many patients relapse due to minimal residual disease (MRD) in vivo or in the graft. Rituximab has the potential to clear both blood and bone marrow of malignant CD20+ cells, prompting this multicenter trial of in vivo purging with rituximab and HDC with APBSCT in China.
Methods: Cyclophosphamide 4g/m2 was used as the mobilization regimen, CY/TBI, BEAM or CBV could be used as HDC at the discretion of the institution. Four infusions of rituximab (375 mg/m2) were given: one day before mobilization, one day before harvesting, one day before transplantation and on day 8 after transplantation. BCL-2/Ig-H translocation was measured as a marker of minimal residual disease in blood or bone marrow before mobilization and during transplantation using real-time quantitative PCR.
Results: Thirty-one patients from 12 centers with histologically proven CD20+ NHL (28 aggressive, 3 indolent NHL) were enrolled. Twenty-four patients were previously untreated, and 7 patients had relapsed disease. Median yields of CD34+ cells and mononuclear cells were 5.9×106/kg and 4.4×108 /kg respectively. Median time to recovery of WBC >1.5×109/L, ANC >0.5×109/L and platelets >20×109/L after APBSCT was 10 days in each case. Median time to platelet recovery >50×109/L was 13 days. Generally, this therapeutic strategy was well tolerated with few side effects attribute to rituximab. All patients achieved a complete remission after APBSCT. At a median-follow-up of 12 months, overall survival and progression-free survival (PFS) are 87% and 73% respectively for all patients. In patients with aggressive NHL, overall survival and PFS are 85% and 73% respectively and in indolent NHL are 100% and 67% respectively. PFS and overall survival were slightly higher in previously untreated compared with relapsed patients (88% vs. 83% for PFS, 73% vs. 69% for overall survival). One of five 5 patients who were initially found to be PCR-positive and achieved PCR-negative status subsequently experienced progression accompanied by a return to PCR positivity. The remaining four patients are still in complete remission and are PCR negative.
Conclusion: These results suggest that the regimen of rituximab combined with HDCT and APBSCT is effective and well tolerated for the treatment of patients with NHL.
A Combination of Rituximab with Chemotherapy in Low Grade Lymphoma.
Authors: Katakkar Suresh B. 
Published: October 2019

Abstract
Introduction: The combination of rituximab with conventional chemotherapy is superior to rituximab therapy alone. Maintanence of chemo-immunotherapy, done for two years at a fixed interval based on pharmacokinetics of Rituximab, may give long term remission improving disease free intervals.
Rationale: MoAb therapy works not only by recruitment of FcR but also by complement dependent cytotoxicity(CDC) and growth arrest and/or apoptosis.
Methodology: This was an open label study. Pts with follicular and diffuse small cleaved-cell NHL stage III and IV were eligible. Induction chemotherapy consists of Cytoxan 650 mg/m2 iv, Vincristine 1mg/m2, Prednisone 50mg/m2 po for 7 days, repeated Q3 weeks. Rituximab was given 375mg/m2 iv Q week for 6 weeks. After 10 weeks of completion of Rituximab, pts were maintained on Rituximab 375 mg/m2 iv Q week for 6 weeks with only one chemotherapy in week 3. CT/PET scan done Q 3 months.
Results: 42 patients; 20 females and 22 males, median age 58. 18 stage III and 24 stage IV. 91%(38/42) went into CR with induction and 1st maintanence therapy. Remaining 4 went into remission after all 6 sessions. Only 3 have relapsed of which 1 is in CR again with reinduction. Thus 39/42 are in CR for a median of 47 months. The toxicity was minimal, with 5% fever chills and hypotension. All responded well to premedication with tagamet and corticosteroid; given iv. 2% incidence of neutropenia. Two patients had sepsis.
Conclusions: 1. The induction and maintanence with Rituximab with addition of chemotherapy is synergistic. 2. It has prolonged the disease free survival. 3. Time to disease progression is prolonged and the final duration of remission is not reached. 4. The toxicity is acceptable, though the treatment is expensive. 5. This chemo-immunotherapy may eliminate microscopic disease and avoid stemcell transplant and associated mortality and morbidity.