bluuebunny/crossref_metadata_2025_split huggingface dataset:
Existence of escape mutant in HTLV-I tax during the development of adult T-cell leukemia
Authors: Furukawa Yoshitaka , Kubota Ryuji , Tara Mitsutoshi , Izumo Shuji , Osame Mitsuhiro 
Published: July 2002

AbstractAlthough Tax protein is the main target of cytotoxic T lymphocyte (CTL) on human T-cell lymphotropic virus type I (HTLV-I)–infected cells, and Tax peptide 11 through 19 binding to HLA-A*02 has been shown to elicit a strong CTL response, there are patients with adult T-cell leukemia (ATL) bearing HLA-A*02. To explore whether there is genetic variation in HTLV-I tax that can escape CTL recognition during the development of ATL, the HTLV-I tax gene was sequenced in 55 patients with ATL, 61 patients with HTLV-I–associated myelopathy/tropical spastic paraparesis (HAM/TSP), and 62 healthy carriers, and it was correlated with the presence of HLA-A*02. First, a premature stop codon in the 5′ half of the tax gene that looses transactivation activity on the viral enhancer was observed in 3 patients with acute and 1 patient with chronic ATL. This stop codon was revealed to emerge after the viral transmission to the patient from sequence analysis in family members with ATL. Second, amino acid change in Tax peptide 11-19 was observed in 3 patients with ATL. CTL assays demonstrated that this altered Tax 11-19 peptide, observed in ATL patients with HLA-A*02, was not recognized by Tax 11-19–specific CTL. Two patients with ATL had large deletions in tax by sequencing, and 5 patients with ATL had deletions in HTLV-I by Southern blotting. These findings suggest that at some stage of ATL development, HTLV-I–infected cells that can escape the host immune system are selected and have a chance to accumulate genetic alterations for further malignant transformation, leading to acute ATL.
Prothrombin protects factor Xa in the prothrombinase complex from inhibition by the heparin-antithrombin complex
Authors: Rezaie Alireza R. 
Published: July 2002

AbstractHeparin is a commonly used anticoagulant drug. It functions primarily by accelerating the antithrombin inhibition of coagulation proteinases, among which factor Xa and thrombin are believed to be the most important targets. There are conflicting results as to whether anticoagulant heparins can catalyze the antithrombin inhibition of factor Xa in the prothrombinase complex (factor Va, negatively charged membrane surfaces, and calcium ion), which is the physiologically relevant form of the proteinase responsible for the activation of prothrombin to thrombin during the blood coagulation process. In this study, a novel assay system was developed to compare the catalytic effect of different molecular-weight heparins in the antithrombin inhibition of factor Xa, either in free form or assembled into the prothrombinase complex during the process of prothrombin activation. This assay takes advantage of the unique property of a recombinant mutant antithrombin, which, similar to the wild-type antithrombin, rapidly inhibits factor Xa, but not thrombin, in the presence of heparin. A direct prothrombinase inhibition assay, monitoring thrombin generation under near physiological concentrations of prothrombin and antithrombin in the presence of therapeutic doses of low- and high-molecular-weight heparins, indicates that factor Xa in the prothrombinase complex is protected from inhibition by antithrombin more than 1000 times, independent of the molecular size of heparin.
Novel vitamin D3 analog, 21-(3-methyl-3-hydroxy-butyl)-19-nor D3, that modulates cell growth, differentiation, apoptosis, cell cycle, and induction of PTEN in leukemic cells
Authors: Hisatake Jun-ichi , O'Kelly James , Uskokovic Milan R. , Tomoyasu Shigeru , Koeffler H. Phillip 
Published: July 2002

Abstract
The active form of vitamin D3, 1,25(OH)2D3, inhibits proliferation and induces differentiation of a variety of malignant cells. A new class of vitamin D3 analogs, having 2 identical side chains attached to carbon-20, was synthesized and the anticancer effects evaluated. Four analogs were evaluated for their ability to inhibit growth of myeloid leukemia (NB4, HL-60), breast (MCF-7), and prostate (LNCaP) cancer cells. All 4 analogs inhibited growth in a dose-dependent manner. Most effective was 21-(3-methyl-3-hydroxy-butyl)-19-nor D3(Gemini-19-nor), which has 2 side chains and removal of the C-19. Gemini-19-nor was approximately 40 625-, 70-, 23-, and 380-fold more potent than 1,25(OH)2D3 in inhibiting 50% clonal growth (ED50) of NB4, HL-60, MCF-7, and LNCaP cells, respectively. Gemini-19-nor (10−8 M) strongly induced expression of CD11b and CD14 on HL-60 cells (90%); in contrast, 1,25(OH)2D3 (10−8 M) stimulated only 50% expression. Annexin V assay showed that Gemini-19-nor and 1,25(OH)2D3 induced apoptosis in a dose-dependent fashion. Gemini-19-nor (10−8 M, 4 days) caused apoptosis in approximately 20% of cells, whereas 1,25(OH)2D3 at the same concentration did not induce apoptosis. Gemini-19-nor increased in HL-60 both the proportion of cells in the G1/G0 phase and expression level of p27kip1. Moreover, Gemini-19-nor stimulated expression of the potential tumor suppressor, PTEN. Furthermore, other inducers of differentiation, all-trans-retinoic acid and 12-O-tetradecanoylphorbol 13-acetate, increased PTEN expression in HL-60. In summary, Gemini-19-nor strongly inhibited clonal proliferation in various types of cancer cells, especially NB4 cells, suggesting that further studies to explore its anticancer potential are warranted. In addition, PTEN expression appears to parallel terminal differentiation of myeloid cells.
The corepressor CtBP interacts with Evi-1 to repress transforming growth factor β signaling
Authors: Izutsu Koji , Kurokawa Mineo , Imai Yoichi , Maki Kazuhiro , Mitani Kinuko , Hirai Hisamaru 
Published: July 2002

AbstractEvi-1 is a zinc finger nuclear protein whose inappropriate expression leads to leukemic transformation of hematopoietic cells in mice and humans. This was previously shown to block the antiproliferative effect of transforming growth factor β (TGF-β). Evi-1 represses TGF-β signaling by direct interaction with Smad3 through its first zinc finger motif. Here, it is demonstrated that Evi-1 represses Smad-induced transcription by recruiting C-terminal binding protein (CtBP) as a corepressor. Evi-1 associates with CtBP1 through one of the consensus binding motifs, and this association is required for efficient inhibition of TGF-β signaling. A specific inhibitor for histone deacetylase (HDAc) alleviates Evi-1–mediated repression of TGF-β signaling, suggesting that HDAc is involved in the transcriptional repression by Evi-1. This identifies a novel function of Evi-1 as a member of corepressor complexes and suggests that aberrant recruitment of corepressors is one of the mechanisms for Evi-1–induced leukemogenesis.
Activation of apoptosis pathways in peripheral blood lymphocytes by in vivo chemotherapy
Authors: Stahnke Karsten , Fulda Simone , Friesen Claudia , Strauß Gudrun , Debatin Klaus-Michael 
Published: July 2002

Abstract
In addition to myelosuppression, anticancer drugs cause rapid and persistent depletion of lymphocytes, possibly by direct apoptosis induction in mature T and B cells. Induction of apoptosis regulators was analyzed in peripheral blood lymphocytes from pediatric patients undergoing first-cycle chemotherapy for solid tumors. In vivo chemotherapy induced a significant increase in lymphocyte apoptosis ex vivo. The activation of initiator caspase-8 and effector caspase-3 and the cleavage of caspase substrates was detected 12 to 48 hours after the onset of therapy. Caspase inhibition by Z-VAD-fmk did not reduce ex vivo lymphocyte apoptosis in all patients, indicating the additional involvement of caspase-independent cell death. No evidence for the involvement of activation-induced cell death was found in the acute phase of lymphocyte depletion as analyzed by activation marker expression and sensitivity for CD95 signaling. Lymphocyte apoptosis in vivo appeared to be predominantly mediated by the mitochondrial pathway because a marked decrease of mitochondrial membrane potential (ΔΨM) was detected after 24 to 72 hours of treatment, preceded by the increased expression of Bax. Interestingly, despite the use of DNA-damaging agents, p53 remained completely undetectable throughout treatment. In contrast, in vitro treatment with cytarabine and etoposide induced p53 protein, CD95 receptor expression, CD95 sensitivity, and CD95 receptor-ligand interaction in stimulated cycling lymphocytes, but no such induction was seen in resting cells. These data suggest that chemotherapy-induced lymphocyte depletion involves distinct mechanisms of apoptosis induction, such as direct mitochondrial and caspase-dependent pathways in resting cells and p53-dependent pathways in cycling lymphocytes.
Gene transfer into murine hematopoietic stem cells with helper-free foamy virus vectors
Authors: Vassilopoulos George , Trobridge Grant , Josephson Neil C. , Russell David W. 
Published: July 2002

Abstract
Gene transfer into hematopoietic stem cells (HSCs) is an ideal treatment strategy for many genetic and hematologic diseases. However, progress has been limited by the low HSC transduction rates obtained with retroviral vectors based on murine leukemia viruses. This study examined the potential of vectors derived from the nonpathogenic human foamy virus (HFV) to transduce human CD34+ cells and murine HSCs. More than 80% of human hematopoietic progenitors present in CD34+ cell preparations derived from cord blood were transduced by a single overnight exposure to HFV vector stocks. Mice that received transduced bone marrow cells expressed the vector-encoded transgene long term in all major hematopoietic cell lineages and in over 50% of cells in some animals. Secondary bone marrow transplants and integration site analysis confirmed that gene transfer occurred at the stem cell level. Transgene silencing was not observed. Thus vectors based on foamy viruses represent a promising approach for HSC gene therapy.
STAT3 is constitutively activated in Hodgkin cell lines
Authors: Kube Dieter , Holtick Udo , Vockerodt Martina , Ahmadi Tahamtan , Haier Birgit , Behrmann Iris , Heinrich Peter C. , Diehl Volker , Tesch Hans 
Published: July 2002

AbstractHodgkin disease (HD) represents a malignant lymphoma in which the putative malignant Hodgkin and Reed-Sternberg cells are rare and surrounded by abundant reactive nonmalignant cells. It has been suggested that cytokines such as interleukin-6 (IL-6) are involved in the pathogenesis of the disease. The expression of the IL-6 receptor (IL-6R) complex and its link to the activation of signal transducers and activators of transcription (STAT) molecules in HD cell lines was investigated. Gel retardation and Western blot analyses revealed a high level of constitutively activated STAT3 in 5 of 7 HD cell lines, which could not be detected in Burkitt lymphoma cell lines. Different levels of IL-6R protein were measured in various HD cell lines: L428 and Dev cells were characterized by very low levels of gp80 and gp130, on KMH2 cells only gp130 but no gp80 was detected, whereas L540, L591, HDLM2, and L1236 were positive for both gp80 and gp130, suggesting a possible autocrine stimulation of STAT3. However, a further increase in STAT3 activation on IL-6 or IL-6/soluble IL-6R stimulation was not observed. Neutralizing monoclonal antibodies against IL-6, gp80, gp130, or both receptor subunits did not affect the proliferation or the constitutive activation of STAT molecules in HD cell lines. However, the tyrosine kinase inhibitor AG490 blocked the constitutive activation of STAT3 and inhibited spontaneous growth of HD tumor cells. The evidence suggests abnormal STAT signaling and growth regulation in Hodgkin cell lines.
Antiphospholipid antibodies and antiphospholipid syndrome in patients presenting with immune thrombocytopenic purpura: a prospective cohort study
Authors: Diz-Küçükkaya Reyhan , Hacıhanefioǧlu Abdullah , Yenerel Mustafa , Turgut Mehmet , Keskin Hüseyin , Nalçacı Meliha , l˙nanç Murat 
Published: July 2002

Abstract
The pathogenetic role and the clinical importance of the presence of antiphospholipid antibodies (APAs) in patients with immune thrombocytopenic purpura (ITP) are not clear. In this study, the prevalence and clinical significance of APAs were investigated in patients with ITP. Eighty-two newly diagnosed ITP patients were prospectively studied. They were evaluated for the presence of lupus anticoagulant (LA) and immunoglobulin G/M anticardiolipin antibodies (ACAs). Thirty-one patients (37.8%) were APA positive at diagnosis. No statistically significant differences were found between the APA-positive and APA-negative groups regarding gender, initial platelet counts, or response to methylprednisolone therapy. After 5 years of follow-up, cumulative thrombosis-free survival of APA-positive (n = 31) and APA-negative (n = 51) ITP patients was 39% and 97.7%, respectively. A significant difference was found between these groups by log-rank test (P = .0004). In addition, LA was an important risk marker for the development of thrombosis in ITP patients. After a median follow-up of 38 months, 14 ITP patients (45%) who had APA positivity developed clinical features (thrombosis or fetal losses) of antiphospholipid syndrome (APS). There were no differences between the APA-positive patients with and without APS regarding the initial platelet counts, response to the therapy, or ACA positivity. The positivity rate for LA was significantly higher in those patients with ITP who developed APS (χ2: P = .0036; relative risk 7.15; 95% confidence interval, 1.7-47). In conclusion, this study indicates that a significant proportion of patients initially presenting with ITP and APA positivity developed APS. In patients with ITP, the persistent presence of APAs is an important risk factor for the development of APS.
Detection of tryptase in cytoplasmic granules of basophils in patients with chronic myeloid leukemia and other myeloid neoplasms
Authors: Samorapoompichit Puchit , Kiener Hans P. , Schernthaner Gerit-Holger , Jordan John-Hendrik , Agis Hermine , Wimazal Friedrich , Baghestanian Mehrdad , Rezaie-Majd Abdolreza , Sperr Wolfgang R. , Lechner Klaus , Valent Peter 
Published: July 2002

AbstractTryptases are serine proteases primarily expressed in mast cells. Normal blood basophils express only trace amounts of the enzyme. However, recent immunohistochemical studies have raised the possibility that neoplastic basophils express significant amounts of tryptase. In this study, tryptase expression was analyzed in normal and neoplastic basophils by immunoelectron microscopy using antitryptase monoclonal antibody G3. Basophils were obtained from patients with chronic myeloid leukemia (CML), idiopathic myelofibrosis (IMF), and myelodysplastic syndrome (MDS), and from healthy donors. Tryptase-immunoreactive material was detected in cytoplasmic granules of basophils in CML, IMF, and MDS. By contrast, normal basophils did not contain significant amounts of tryptase by immunoelectron microscopy. As assessed by reverse transcription-polymerase chain reaction, neoplastic basophils contained messenger RNA (mRNA) for α-tryptase, but no β-tryptase mRNA. In summary, these data provide evidence that neoplastic basophils in CML, IMF, and MDS can express detectable amounts of tryptase. Therefore, tryptase should not be regarded as specific for mast cells when neoplastic myeloid cells are analyzed.
HIV-1 Nef activates STAT1 in human monocytes/macrophages through the release of soluble factors
Authors: Federico Maurizio , Percario Zulema , Olivetta Eleonora , Fiorucci Gianna , Muratori Claudia , Micheli Alessandro , Romeo Giovanna , Affabris Elisabetta 
Published: July 2002

AbstractMonocytes/macrophages play a predominant role in the immunologic network by secreting and reacting to a wide range of soluble factors. Human immunodeficiency virus (HIV) infection leads to deep immunologic dysfunctions, also as a consequence of alterations in the pattern of cytokine release. Recent studies on in vivo models demonstrated that the expression of HIV Nef alone mimics many pathogenetic effects of HIV infection. In particular, Nef expression in monocytes/macrophages has been correlated with remarkable modifications in the pattern of secreted soluble factors, suggesting that the interaction of Nef with monocytes/macrophages plays a role in the pathogenesis of acquired immunodeficiency syndrome (AIDS). This study sought to define possible alterations in intracellular signaling induced by Nef in monocytes/macrophages. Results demonstrate that HIV-1 Nef specifically activates both α and β isoforms of the signal transducer and activator of transcription 1 (STAT1). This was observed both by infecting human monocyte-derived macrophages (MDMs) with HIV-1 deletion mutants, and by exploiting the ability of MDMs to internalize soluble, recombinant Nef protein (rNef). STAT1-α activation occurs on phosphorylation of both C-terminal Tyr701 and Ser727 and leads to a strong binding activity. Nef-dependent STAT1 activation is followed by increased expression of both STAT1 and interferon regulatory factor-1, a transcription factor transcriptionally regulated by STAT1 activation. It was also established that Nef-induced STAT1- α/β activation occurs through the secretion of soluble factors. Taken together, the results indicate that HIV-1 Nef could interfere with STAT1-governed intracellular signaling in human monocytes/macrophages.
Alveolar macrophage deficiency in osteopetrotic mice deficient in macrophage colony-stimulating factor is spontaneously corrected with age and associated with matrix metalloproteinase expression and emphysema
Authors: Shibata Yoko , Zsengeller Zsuzsanna , Otake Kazuhisa , Palaniyar Nades , Trapnell Bruce C. 
Published: July 2002

AbstractMacrophage colony-stimulating factor (M-CSF) is one of several hematologic growth factors capable of regulating the survival, proliferation, and differentiation of macrophages, but its role in modulation of the accumulation and function of alveolar macrophages (AMs) in vivo is not well defined. Osteopetrotic (Op/Op) mice have no detectable M-CSF and show variable tissue-specific reductions in macrophage numbers. It was hypothesized that AMs would be decreased in number and have altered function in Op/Op mice because of the absence of M-CSF. Lung macrophages identified by Mac-3 staining in lung sections were decreased in number in 20-day-old Op/Op mice (P < .001) but not Op/Op mice older than 4 months (P = .68) compared with findings in age-matched littermate controls. The numbers of AMs recovered by bronchoalveolar lavage (BAL) were also reduced in young but not adult Op/Op mice compared with controls. Expression of interleukin-3 (IL-3) was increased in the lungs of Op/Op mice compared with controls as determined by quantification of IL-3 cytokine levels (P = .04), bioactivity (P = .02), and messenger RNA transcript levels. AMs of Op/Op mice spontaneously released higher levels of matrix metalloproteinases (MMPs) than AMs of controls as determined by immunohistochemical staining of AMs and zymographic assessment of BAL fluid and AM lysates. Consistent with an increased release of MMP, Op/Op mice had abnormal elastin deposition and spontaneously developed emphysema in the absence of molecular or cellular evidence of lung inflammation. These data show that the AM deficiency observed in young Op/Op mice is spontaneously corrected with age and is associated with increased lung levels of IL-3, spontaneous MMP expression by AMs, and destruction of lung tissue.
CD38 expression and immunoglobulin variable region mutations are independent prognostic variables in chronic lymphocytic leukemia, but CD38 expression may vary during the course of the disease
Authors: Hamblin Terry J. , Orchard Jenny A. , Ibbotson Rachel E. , Davis Zadie , Thomas Peter W. , Stevenson Freda K. , Oscier David G. 
Published: July 2002

Abstract
Although the presence or absence of somatic mutations in the immunoglobulin variable region (IgVH) genes in chronic lymphocytic leukemia (B-CLL) identifies subtypes with very different prognoses, the assay is technically complex and unavailable to most laboratories. CD38 expression has been suggested as a surrogate marker for the 2 subtypes. IgVHmutations and CD38 expression in 145 patients with B-CLL with a long follow-up were compared. The 2 assays gave discordant results in 41 patients (28.3%). Multivariate analysis demonstrated that Binet stage,IgVH mutations and CD38 were independent prognostic indicators. Median survival time in patients whose cells had unmutated IgVH genes and expressed CD38 was 8 years; in those with mutated IgVHgenes not expressing CD38, it was 26 years. For those with discordant results, median survival time was 15 years. Thus, although CD38 expression does not identify the same 2 subsets as IgVHmutations in CLL, it is an independent risk factor that can be used with IgVH mutations and clinical stage to select patients with B-CLL with the worst prognoses. Using cryopreserved cells taken at intervals during the course of the disease, however, changes of CD38 expression over time were demonstrated in 10 of 41 patients. Causes of the variation of CD38 expression require further study. Additional prospective studies are required for comparing CD38 expression with other prognostic factors and for taking sequential measurements during the course of the disease.
Neural networks as an intelligence amplification tool: A review of applications
Authors: Poulton Mary M. 
Published: July 2002

The sophisticated algorithms we use to process, analyze, and interpret geophysical data automate tasks we used to do by hand, transform data into domains where patterns are more obvious, and allow us to calculate quantities where we used to rely on intuition or back‐of‐envelope estimates. But, the crux of the exploration problem is still interpretation—associating abstract patterns with geologic formations of economic value. Artificial neural networks are able to couple the speed and efficiency of the computer with the pattern recognition and association capabilities of the brain to aid the exploration process. The key concept to understand in the application of neural network technology is that they should not be used as an artificial intelligence tool to replace a human interpreter; rather, neural networks are an intelligence amplification toolkit that allows the interpreter to focus on the important information.More than 102 neural network papers have been published by SEG since 1988, and more than 550 neural network papers pertaining to any aspect of geophysics were published in that same time period. Neural network applications in exploration geophysics can generally be divided into two eras. The focus through 1994 was largely on learning what neural networks could do with different data sets, and how to prepare data for them and analyze the results. Networks were usually trained with synthetic data and then tested with field data. The second era, from 1995 to the present, has focused on some specific application areas such as reservoir characterization. The current emphasis is to integrate neural networks within a comprehensive interpretation scheme instead of as a stand‐alone application. Neural network technology has helped us turn data into information by allowing us to find nontrivial correlations between geophysical data and petrophysical properties; relate detailed changes in wavelet morphology to small‐scale changes in lithology; and find features in the wavelets that allow us to locate first breaks, track horizons, identify gas chimneys, or trace faults; and attenuate multiples. As the science and engineering of data acquisition progresses, neural networks will play an increasingly vital role in helping us find relevant information in the vast streams of data under the constraints of lower costs, less time, and fewer people.