bluuebunny/crossref_metadata_2025_split huggingface dataset:
The Tyrosine Kinase Inhibitor CGP57148B Selectively Inhibits the Growth of BCR-ABL–Positive Cells
Authors: Deininger Michael W.N. , Goldman John M. , Lydon Nicholas , Melo Junia V. 
Published: October 2019

Abstract
The Philadelphia chromosome found in virtually all cases of chronic myeloid leukemia (CML) and in about one third of the cases of adult acute lymphoblastic leukemia is formed by a reciprocal translocation between chromosomes 9 and 22 that results in the fusion of BCR and ABL genetic sequences. This BCR-ABL hybrid gene codes for a fusion protein with deregulated tyrosine kinase activity that can apparently cause malignant transformation. CGP57148B, a 2-phenylaminopyrimidine derivative, has been shown to selectively inhibit the tyrosine kinase of ABL and BCR-ABL. We report here that this compound selectively suppresses the growth of colony-forming unit–granulocyte/macrophage (CFU-GM) and burst-forming unit–erythroid derived from CML over a 2-logarithmic dose range with a maximal differential effect at 1.0 μmol/L. However, almost all CML colonies that grow in the presence of 1.0 μmol/L CGP57148B are BCR-ABL–positive, which may reflect the fact that residual normal clonogenic myeloid precursors are infrequent in most patients with CML. We also studied the effects of CGP57148B on hematopoietic cell lines. Proliferation was suppressed in most of the BCR-ABL–positive lines; all five BCR-ABL–negative lines were unaffected. We conclude that this new agent may have significant therapeutic applications.
Idiotype Vaccines for Non-Hodgkin's Lymphoma Induce Polyclonal Immune Responses That Cover Mutated Tumor Idiotypes: Comparison of Different Vaccine Formulations
Authors: Caspar Clemens B. , Levy Shoshana , Levy Ronald 
Published: October 2019

AbstractThe idiotype (Id) of the Ig expressed on the surface of non-Hodgkin's lymphoma cells is a suitable target for immunotherapy. Indeed, treatment with monoclonal anti-Id antibodies (Abs) can induce long-lasting clinical remissions. However, some of the treated patients relapse with a tumor expressing Ig with point mutations in the idiotope recognized by the particular monoclonal antibody (MoAb). The alternative approach of active immunization with tumor Id can cure the disease in mice with established tumors and is now being studied in clinical trials. Here, we tested the hypothesis that active immunization with the idiotype would evoke a polyclonal immune response that would cover mutated tumor variants. As a test system, we chose the tumor from a patient who had achieved a complete remission after therapy with anti-Id Ab but subsequently relapsed with a mutated tumor variant no longer binding the treatment Ab. Mice were immunized with proteins and genetic vaccines derived from the original tumor, including (1) Id-keyhole limpet hemocyanin protein, (2) Id single-chain variable fragment (scFv) granulocyte-macrophage colony-stimulating factor (GM-CSF) protein, (3) DNA encoding the Id, and (4) an adenovirus encoding the Id. All immunized mice developed a specific immune response detecting tumor-derived Id proteins from the original tumor and from all tumor variants. We conclude that active immunization with tumor Id can induce a polyclonal immune response and therefore may prevent the escape of mutated tumor variants.
Bone Resorption in Multiple Myeloma and in Monoclonal Gammopathy of Undetermined Significance: Quantification by Urinary Pyridinium Cross-Links of Collagen
Authors: Pecherstorfer Martin , Seibel Markus J. , Woitge Henning W. , Horn Eva , Schuster Judith , Neuda Jane , Sagaster Peter , Köhn Horst , Bayer Peter , Thiébaud Daniel , Ludwig Heinz 
Published: October 2019

AbstractTo quantify osseous breakdown in multiple myeloma (MM), monoclonal gammopathy of undetermined significance (MGUS), and benign osteoporosis, we measured urinary levels of pyridinium cross-links of collagen in 50 patients with newly diagnosed and untreated MM, 40 patients with MGUS, 40 untreated patients with osteoporotic vertebral fractures, and 64 healthy adults. Ion-paired, reverse-phase high-performance liquid chromatography (HPLC) was used to measure total urinary excretion of pyridinoline (h-PYD) and deoxypyridinoline (h-DPD). Urinary excretion of free immunoreactive deoxypyridinoline (i-DPD) was determined with an enzyme immunoassay. MM patients had significantly (P < .0001) higher levels of h-PYD, h-DPD, and i-DPD than the healthy adults, patients with MGUS, or patients with osteoporosis. The MGUS and osteoporosis groups presented with elevated (P < .05) levels of urinary pyridinium cross-links when compared with healthy controls. In 20 MM patients who subsequently received chemotherapy, the percent changes in i-DPD did not correlate with the changes in the monoclonal protein. In one of three patients experiencing a transition of initial MGUS into stage I MM, i-DPD increased above the upper limit of the normal range. In 13 patients with stable MGUS, i-DPD remained normal in repeated measurements. Based on the upper limits of the normal range, the sensitivity of urinary pyridinium cross-links in stage I and II MM was low (<50%), but it was between 78% (h-DPD) and 93% (i-DPD) in stage III MM. Specificity in patients with MGUS was between 87% (h-PYD) and 97% (h-DPD). In conclusion, determining the urinary excretion of pyridinium cross-links seems to be a promising noninvasive and thus easily repeatable method for evaluating the actual degree of osseous breakdown. Although measurement of pyridinium cross-link levels is not useful in discriminating patients with MGUS from early-stage myeloma patients, determination of i-DPD levels may contribute importantly to clinical guidance, since increased i-DPD levels seem to identify patients who are particularly likely to benefit from osteoclast-inhibiting drugs such as bisphosphonates. The fact that in a number of patients paraprotein concentrations and i-DPD levels did not change in parallel but instead diverged strongly after chemotherapy might explain the observation that bone lesions sometimes progress even in patients who achieve complete remission.
Natural History of GBV-C/Hepatitis G Virus Infection Through the Follow-Up of GBV-C/Hepatitis G Virus–Infected Blood Donors and Recipients Studied by RNA Polymerase Chain Reaction and Anti-E2 Serology
Authors: Lefrère Jean-Jacques , Loiseau Pascale , Maury Jacqueline , Lasserre Jacqueline , Mariotti Martine , Ravera Nadine , Lerable Joelle , Lefèvre Guillaume , Morand-Joubert Laurence , Girot Robert 
Published: October 2019

Abstract
The aims of this study were to determine the outcome and the natural history of GBV-C/hepatitis G virus (HGV) infection and to establish the frequency of acute or persistent infections in multiply-transfused individuals and blood donors. We used a GBV-C/HGV RNA polymerase chain reaction (PCR) and an assay evidencing antibodies to the envelop protein E2, which is considered a marker for virus clearance. Among 16 PCR-positive recipients, 11 were still positive for GBV-C/HGV RNA at the end of the study period; six of the 16 recipients were GBV-C/HGV infected during the study period and thus had a well-defined date of infection. The 16 patients were shown to carry GBV-C/HGV RNA over a mean period of 4.4 years, for a mean observational period (defined as the follow-up period since the first sample positive for GBV-C/HGV RNA) of 5.3 years. Within the limits of the study period, the patients with a well-defined date of infection were positive for GBV-C/HGV RNA during a mean period of 4.7 years. If defined by the presence of GBV-C/HGV RNA for at least 6 months, the persistent infection rate was 100% in this recipient cohort. Serum anti-E2 antibody was evidenced at least once in five (31.2%) recipients and, except in one case, became detectable after the loss of GBV-C/HGV RNA. Among the 11 blood donors, all were still positive for GBV-C/HGV RNA after a mean follow-up period of 7.7 months. The persistent infection rate was 100% in this donor cohort. Once acquired, the infection to GBV-C/HGV generally tends to persist in immunocompetent patients.
BCL-2 Expression Correlates With Lower Proliferative Activity in the Intermediate- and High-Grade Non-Hodgkin's Lymphomas: An Eastern Cooperative Oncology Group and Southwest Oncology Group Cooperative Laboratory Study
Authors: Winter Jane N. , Andersen Janet , Reed John C. , Krajewski Stanislaw , Variakojis Daina , Bauer Kenneth D. , Fisher Richard I. , Gordon Leo I. , Oken Martin M. , Jiang Shuwei , Jeffries David , Domer Peter 
Published: October 2019

AbstractAn inverse relationship between BCL-2 expression and cell cycle transition has been suggested by recent studies in murine models. To investigate the clinical relevance of these laboratory studies, a group of 116 paraffin-embedded non-Hodgkin's lymphoma (NHL) biopsy specimens (Working Formulation Groups D-H, and J) from a cooperative group study of cellular DNA content were analyzed for the 14;18 translocation using polymerase chain reaction (PCR)-based methods and, if sufficient tissue remained, for BCL-2 and BAXexpression by immunohistochemistry. The results of these studies were then compared with the results of the previously performed flow cytometric analysis of ploidy and proliferative activity (S-phase-fraction). BCL-2 expression was inversely associated with proliferative activity (P = .001; n = 41), but there was no association between staining for Bax and %S-phase. Ploidy was not associated with either BCL-2 or BAX expression. The t(14;18) was detected in 21 of the 54 cases in which PCR-amplifiable DNA was recovered; 20 of these occurred at the major breakpoint region and 1 at the minor breakpoint region. High levels of BCL-2 orBAX expression occurred independently of t(14;18). There was no association between t(14;18) and either ploidy or proliferative activity. The inverse relationship between BCL-2 expression and proliferative activity in the intermediate- and high-grade NHLs is consistent with recent studies suggesting that Bcl-2 both retards entry into the cell cycle and inhibits apoptosis.
HBED: A Potential Alternative to Deferoxamine for Iron-Chelating Therapy
Authors: Bergeron Raymond J. , Wiegand Jan , Brittenham Gary M. 
Published: October 2019

AbstractTo examine the potential clinical usefulness of the hexadentate phenolic aminocarboxylate iron chelatorN,N-bis(2-hydroxybenzyl)ethylenediamine-N,N-diacetic acid (HBED) for the chronic treatment of transfusional iron overload, we compared the iron excretion induced by subcutaneous (SC) injection of HBED and deferoxamine (DFO), the reference chelator, in rodents and primates. In the non–iron-overloaded, bile-duct–cannulated rat, a single SC injection of HBED, 150 μmol/kg, resulted in a net iron excretion that was more than threefold greater than that after the same dose of DFO. In the iron-loaded Cebus apella monkey, a single SC injection of HBED, 150 μmol/kg, produced a net iron excretion that was more than twice that observed after the same dose of SC DFO. In patients with transfusional iron overload, SC injections of HBED may provide a much needed alternative to the use of prolonged parenteral infusions of DFO.
Prognostic implications of differences in telomere length between normal and malignant cells from patients with chronic myeloid leukemia measured by flow cytometry
Authors: Brümmendorf Tim H. , Holyoake Tessa L. , Rufer Nathalie , Barnett Michael J. , Schulzer Michael , Eaves Connie J. , Eaves Allen C. , Lansdorp Peter M. 
Published: October 2019

AbstractChronic myeloid leukemia (CML) is a clonal, multilineage myeloproliferative disorder characterized by the Philadelphia chromosome (Ph) and a marked expansion of myeloid cells. Previous studies have indicated that the telomere length in blood cells may indicate their replicative history. However, the large variation in telomere length between individuals complicates the use of this parameter in CML and other hematologic disorders. To circumvent this problem, we compared the telomere length in peripheral blood or bone marrow cells with purified normal (Ph−) T lymphocytes from the same CML patient using fluorescence in situ hybridization and flow cytometry. Overall telomere fluorescence was significantly reduced in Ph+ cells from patients with CML compared to blood leukocytes from normal individuals (P &lt; 0.001) or normal (Ph−) T lymphocytes from the same individuals (n = 51, P &lt; 0.001). Cells from patients in accelerated phase or blast phase (AP/BP) showed significantly shorter average telomere length than cells from patients in chronic phase (CP,P = 0.02) or cytogenetic remission (CR,P = 0.03). Patients in CP who subsequently developed BP within 2 years had significantly shorter telomeres than those who did not develop BP for at least 2 years (P &lt; 0.05). Accelerated replication-dependent telomere shortening in Ph+ versus Ph− leukocytes supports previous evidence that Ph+ stem cells cycle more actively than their counterparts in normal individuals. Our data further suggest that telomere shortening may serve as a surrogate marker of disease progression in patients with CP CML, supporting a mechanistic link between CML stem cell turnover, genetic instability, and malignant evolution in this disease. (Blood. 2000;95:1883-1890)
Engagement of the α2β1 integrin inhibits Fas ligand expression and activation-induced cell death in T cells in a focal adhesion kinase-dependent manner
Authors: Aoudjit Fawzi , Vuori Kristiina 
Published: October 2019

AbstractT-cell receptor (TCR)-mediated apoptosis, also known as activation-induced cell death (AICD), plays an important role in the control of immune response and in the development of T-cell repertoire. Mechanistically, AICD has been largely attributed to the interaction of Fas ligand (Fas-L) with its cell surface receptor Fas in activated T cells. Signal transduction mediated by the integrin family of cell adhesion receptors has been previously shown to modulate apoptosis in a number of different cell types; in T cells, integrin signaling is known to be important in cellular response to antigenic challenge by providing a co-stimulatory signal for TCR. In this study we demonstrate that signaling via the collagen receptor 2β1 integrin specifically inhibits AICD by inhibiting Fas-L expression in activated Jurkat T cells. Engagement of the 2β1 integrin with monoclonal antibodies or with type I collagen, a cognate ligand for 2β1, reduced anti-CD3 and PMA/ionomycin-induced cell death by 30% and 40%, respectively, and the expression of Fas-L mRNA by 50%. Further studies indicated that the 2β1-mediated inhibition of AICD and Fas-L expression required the focal adhesion kinase FAK, a known component in the integrin signaling pathways. These results suggest a role for the 2β1 integrin in the control of homeostasis of immune response and T-cell development.
A monoclonal antibody (MUM1p) detects expression of the MUM1/IRF4 protein in a subset of germinal center B cells, plasma cells, and activated T cells
Authors: Falini Brunangelo , Fizzotti Marco , Pucciarini Alessandra , Bigerna Barbara , Marafioti Teresa , Gambacorta Marcello , Pacini Roberta , Alunni Cristina , Natali–Tanci Laura , Ugolini Barbara , Sebastiani Carla , Cattoretti Giorgio , Pileri Stefano , Dalla-Favera Riccardo , Stein Harald 
Published: October 2019

AbstractA new monoclonal antibody (MUM1p) was used to study the cell/tissue expression of human MUM1/IRF4 protein, the product of the homologous gene involved in the myeloma-associated t(6;14) (p25;q32). MUM1 was expressed in the nuclei and cytoplasm of plasma cells and a small percentage of germinal center (GC) B cells mainly located in the “light zone.” Its morphologic spectrum ranged from that of centrocyte to that of a plasmablast/plasma cell, and it displayed a phenotype (MUM1+/Bcl-6−/Ki67−) different from that of most GC B cells (MUM1−/Bcl-6+/Ki67+) and mantle B cells (MUM1−/Bcl-6−/Ki67−). Polymerase chain reaction (PCR) analysis of single MUM1+cells isolated from GCs showed that they contained rearranged Ig heavy chain genes with a varying number of VHsomatic mutations. These findings suggest that these cells may represent surviving centrocytes and their progeny committed to exit GC and to differentiate into plasma cells. MUM1 was strongly expressed in lymphoplasmacytoid lymphoma, multiple myeloma, and approximately 75% of diffuse large B-cell lymphomas (DLCL-B). Unlike normal GC B cells, in which the expression of MUM1 and Bcl-6 were mutually exclusive, tumor cells in approximately 50% of MUM1+ DLCL-B coexpressed MUM1 and Bcl-6, suggesting that expression of these proteins may be deregulated. In keeping with their proposed origin from GC B cells, Hodgkin and Reed–Sternberg cells of Hodgkin's disease consistently expressed MUM1. MUM1 was detected in normal and neoplastic activated T cells, and its expression usually paralleled that of CD30. These results suggest that MUM1 is involved in the late stages of B-cell differentiation and in T-cell activation and is deregulated in DLCL-B.
Deletions of chromosome 5q13.3 and 17p loci cooperate in myeloid neoplasms
Authors: Castro Patricia D. , Liang Jan C. , Nagarajan Lalitha 
Published: October 2019

AbstractNonrandom interstitial deletions and monosomy of chromosomes 5, 7, and 17 in refractory myelodysplasia (MDS) and acute myelogenous leukemia (AML) suggest a multistep pathway that culminates in aggressive clinical course. Because cytogenetic studies frequently identify chromosome 5 and 17 deletions within a single clone, we searched for allele loss for 5q loci and TP53 gene mutations in the same leukemic samples. Cosegregating deletions of chromosomes 5 and 17 were found to specifically include the 5q13.3 interval between the lociD5S672 and D5S620/D5S626, a locus hypothesized to harbor a tumor suppressor gene1 and the TP53 gene on 17p. A rare patient with secondary refractory MDS and an unbalanced translocation [der(5;17)], which resulted in deletions of the 5q13.3-qter and 17p loci, provided clues on the sequence of genetic alterations. Serial molecular analysis of this patient revealed a dysplastic clone with der(5;17), which gave rise to a leukemic clone on acquiring an inactivating mutation of TP53. Our findings are consistent with functional cooperation between a putative tumor suppressor gene at 5q13.3 that contributes toward the progression of early stages of MDS, and the TP53 gene when mutated, causes transformation to AML.
Recombination events between the p47-phoxgene and its highly homologous pseudogenes are the main cause of autosomal recessive chronic granulomatous disease
Authors: Roesler Joachim , Curnutte John T. , Rae Julie , Barrett David , Patino Pablo , Chanock Stephen J. , Goerlach Agnes 
Published: October 2019

AbstractChronic granulomatous disease (CGD) is an inherited disease caused by defects in the superoxide-generating nicotinamide adenine dinucleotide phosphate (NADPH) oxidase of phagocytes. Genetic lesions in any of 4 components of this antimicrobial enzyme have been detected. Family-specific mutations are found in 3 of 4 forms of CGD due to deficiencies of the gp91-phox, p22-phox, andp67-phox genes. In p47-phox–deficient CGD (autosomal recessive form A47°) patients, a GT deletion (▵GT) at the beginning of exon 2 of the p47-phox gene has been reported in 19 of 20 alleles. This GT deletion is also characteristic for the recently identified p47-phox pseudogenes. To explore a possible link between these findings, a sequence analysis of 28 unrelated, racially diverse A47° CGD patients and 37 healthy individuals was performed. The GT deletion in exon 2 was present on all alleles in 25 patients. Only 3 patients but all healthy individuals contained the GTGT and ▵GT sequences. A total of 22 patients carried additional pseudogene-specific intronic sequences on all alleles, either only in intron 1 or in intron 1 and intron 2, which lead to different types of chimeric DNA strands. It is concluded that recombination events between the p47-phox gene and its highly homologous pseudogenes result in the incorporation of ▵GT into the p47-phox gene, thereby leading to the high frequency of GT deletion in A47° CGD patients.
Autologous transplantation of ex vivo expanded bone marrow cells grown from small aliquots after high-dose chemotherapy for breast cancer
Authors: Stiff Patrick , Chen Bohao , Franklin Wilbur , Oldenberg David , Hsi Eric , Bayer Robert , Shpall Elizabeth , Douville Judy , Mandalam Ramkumar , Malhotra Deepak , Muller Thomas , Armstrong R. Douglas , Smith Alan 
Published: October 2019

Abstract
The collection of small aliquots of bone marrow (BM), followed by ex vivo expansion for autologous transplantation may be less morbid, and more cost-effective, than typical BM or blood stem cell harvesting. Passive elimination of contaminating tumor cells during expansion could reduce reinoculation risks. Nineteen breast cancer patients underwent autotransplants exclusively using ex vivo expanded small aliquot BM cells (900-1200 × 106). BM was expanded in media containing recombinant flt3 ligand, erythropoietin, and PIXY321, using stromal-based perfusion bioreactors for 12 days, and infused after high-dose chemotherapy. Correlations between cell dose and engraftment times were determined, and immunocytochemical tumor cell assays were performed before and after expansion. The median volume of BM expanded was 36.7 mL (range 15.8-87.0). Engraftment of neutrophils greater than 500/μL and platelets greater than 20 000/μL were 16 (13-24) and 24 (19-45) days, respectively; 1 patient had delayed platelet engraftment, even after infusion of back-up BM. Hematopoiesis is maintained at 24 months, despite posttransplant radiotherapy in 18 of the 19 patients. Transplanted CD34+/Lin−(lineage negative) cell dose correlated with neutrophil and platelet engraftment, with patients receiving greater than 2.0 × 105 CD34+/Lin− cells per kilogram, engrafting by day 28. Tumor cells were observed in 1 of the 19 patients before expansion, and in none of the 19 patients after expansion. It is feasible to perform autotransplants solely with BM cells grown ex vivo in perfusion bioreactors from a small aliquot. Engraftment times are similar to those of a typical 1000 to 1500 mL BM autotransplant. If verified, this procedure could reduce the risk of tumor cell reinoculation with autotransplants and may be valuable in settings in which small stem cell doses are available, eg, cord blood transplants.