bluuebunny/crossref_metadata_2025_split huggingface dataset:
Arsenic trioxide induces apoptosis in human T-cell leukemia virus type 1– and type 2–infected cells by a caspase-3–dependent mechanism involving Bcl-2 cleavage
Authors: Mahieux Renaud , Pise-Masison Cynthia , Gessain Antoine , Brady John. N. , Olivier René , Perret Emmanuelle , Misteli Tom , Nicot Christophe 
Published: October 2002

Abstract
Treatment of patients with adult T-cell leukemia–lymphoma (ATLL) using conventional chemotherapy has limited benefit because human T-cell leukemia virus type 1 (HTLV-1) cells are resistant to most apoptosis-inducing agents. The recent report that arsenic trioxide induces apoptosis in HTLV-1–transformed cells prompted investigation of the mechanism of action of this drug in HTLV-1 and HTLV-2 interleukin-2–independent T cells and in HTLV-1–immortalized cells or in ex vivo ATLL samples. Fluorescence-activated cell sorter analysis, fluorescence microscopy, and measures of mitochondrial membrane potential (ΔΨm) demonstrated that arsenic trioxide alone was sufficient to induce programmed cell death in all HTLV-1 and -2 cells tested and in ATLL patient samples. IκB-α phosphorylation strongly decreased, and NF-κB translocation to the nucleus was abrogated. Expression of the antiapoptotic protein Bcl-XL, whose promoter is NF-κB dependent, was down-regulated. The collapse of ΔΨm and the release of cytochrome c to the cytosol resulted in the activation of caspase-3, as demonstrated by the cleavage of PARP. A specific caspase-3 inhibitor (Ac-DEVD-CHO) could reverse this phenotype. The antiapoptotic factor Bcl-2 was then cleaved, converting it to a Bax-like death effector. These results demonstrated that arsenic trioxide induces apoptosis in HTLV-1– and -2–infected cells through activation of the caspase pathway.
Role of protein kinase C ζ isoform in Fas resistance of immature myeloid KG1a leukemic cells
Authors: de Thonel Aurélie , Bettaı̈eb Ali , Jean Christine , Laurent Guy , Quillet-Mary Anne 
Published: October 2002

AbstractLeukemic CD34+ immature acute myeloid leukemia (AML) cells express Fas receptor but are frequently resistant to Fas agonistic reagents. Fas plays an important role in T-cell–mediated cytotoxicity, and recently it has been suggested that altered Fas signaling may contribute to drug resistance. Therefore, Fas resistance could be one of the mechanisms by which AML progenitors escape chemotherapy or T-cell–based immune intervention. However, the molecular mechanism of Fas resistance in AML cells has not been identified. Fas signaling can be interrupted at 3 mains levels: Fas clustering, alteration of death-inducing-signaling-complex (DISC) formation, and effector caspase inhibition of downstream caspase-8. This study shows that in the Fas-resistant CD34+CD38− KG1a cells, Fas agonists resulted in Fas aggregation but not in caspase-8 activation, related to a defect in DISC formation. However, pretreatment with chelerythrin, but not with calphostin C, resulted in the restoration of Fas-induced caspase-8 activation and cytotoxicity, suggesting that some atypical protein kinase C (PKC) isoforms contributed to the lack of DISC formation. Indeed, treatment with antisense oligonucleotides directed against PKCζ and enforced expression of Par-4, a negative regulator of PKCζ activity, restored Fas-induced caspase-8 activity and apoptosis. Moreover, it was found that PKCζ interacts with FADD and that PKCζ immunoextracts prepared from KG1a cells are able to phosphorylate FADD in vitro, whereas this phosphorylation is dramatically reduced in Par-4 transfectant cells. In conclusion, it is suggested that in AML cells, PKCζ plays an important role in Fas resistance by inhibiting DISC formation, possibly by phosphorylating FADD.
A novel Notch ligand, Dll4, induces T-cell leukemia/lymphoma when overexpressed in mice by retroviral-mediated gene transfer
Authors: Yan Xiao-Qiang , Sarmiento Ulla , Sun Yu , Huang Guo , Guo Jane , Juan Todd , Van Gwyneth , Qi Mei-Ying , Scully Sheila , Senaldi Giorgio , Fletcher Frederick A. 
Published: October 2002

AbstractNotch receptors mediate cell-fate decisions through interaction with specific ligands during development. The biological role of a novel Notch ligand, Dll4, in mice was explored by reconstituting lethally irradiated mice with bone marrow (BM) cells transduced with Dll4 retroviral vector. White blood cell and lymphocyte counts in Dll4-overexpressing mice were reduced at the early stage of reconstitution but increased significantly at approximately 10 weeks after BM transplantation. BM, spleen, lymph nodes, and peripheral blood ofDll4-overexpressing mice contained predominantly CD4+CD8+ T cells and virtually lacked B cells. The Dll4-overexpressing mice eventually developed a lethal phenotype that was characterized by the progression of a T-cell lymphoproliferative disease (restricted to BM and lymphoid tissues) to transplantable monoclonal T-cell leukemia/lymphoma scattered to multiple organs. Results suggest that the interaction of Dll4with Notch1 may provide key signals for T-cell development.
Multiple cis elements regulate an alternative splicing event at 4.1R pre-mRNA during erythroid differentiation
Authors: Deguillien Mireille , Huang Shu-Ching , Morinière Madeleine , Dreumont Natacha , Benz Edward J. , Baklouti Faouzi 
Published: October 2002

AbstractThe inclusion of exon 16 in the mature protein 4.1R messenger RNA (mRNA) is a critical event in red blood cell membrane biogenesis. It occurs during late erythroid development and results in inclusion of the 10-kd domain needed for stabilization of the spectrin/actin lattice. In this study, an experimental model was established in murine erythroleukemia cells that reproduces the endogenous exon 16 splicing patterns from a transfected minigene. Exon 16 was excluded in predifferentiated and predominantly included after induction. This suggests that the minigene contained exon and abutting intronic sequences sufficient for splicing regulation. A systematic analysis of the cis-acting regulatory sequences that reside within the exon and flanking introns was performed. Results showed that (1) the upstream intron of 4.1R pre-mRNA is required for exon recognition and it displays 2 enhancer elements, a distal element acting in differentiating cells and a proximal constitutive enhancer that resides within the 25 nucleotides preceding the acceptor site; (2) the exon itself contains a strong constitutive splicing silencer; (3) the exon has a weak 5′ splice site; and (4) the downstream intron contains at least 2 splicing enhancer elements acting in differentiating cells, a proximal element at the vicinity of the 5′ splice site, and a distal element containing 3 copies of the UGCAUG motif. These results suggest that the interplay between negative and positive elements may determine the inclusion or exclusion of exon 16. The activation of the enhancer elements in late erythroid differentiation may play an important role in the retention of exon 16.
Correction of cross-linker sensitivity of Fanconi anemia group F cells by CD33-mediated protein transfer
Authors: Holmes Rebecca K. , Harutyunyan Karine , Shah Maulik , Joenje Hans , Youssoufian Hagop 
Published: October 2002

AbstractStudies have previously described the feasibility of receptor-mediated protein transfer in a cell culture model of Fanconi anemia (FA) group C. This study explores the versatility of this approach by using an antibody single-chain fusion protein to correct the phenotypic defect in FA group F cells. A 68.5-kd chimeric protein (His-M195FANCF) was expressed, consisting of a His tag, a single-chain antibody to the myeloid antigen CD33, and the FANCF protein, as well as a 43-kd His-FANCF fusion protein lacking the antibody motif, inEscherichia coli. The nickel-agarose–purified His-M195FANCF protein bound specifically to the surface of HeLa cells transfected with CD33 and internalized through vesicular structures. The fusion protein, but not CD33, sorted to the nucleus, consistent with the known nuclear localization of FANCF. No similar binding or internalization was observed with His-FANCF. Pretreatment of the transfected cells with chloroquine abolished nuclear accumulation, but there was little change with brefeldin A, indicating a minimal if any role for the Golgi apparatus in mediating transport from endosomes to the cytosol and the nucleus. The intracellular half-life of His-M195FANCF was approximately 160 minutes. Treatment of CD33-transfected FA group F lymphoblastoid cells with 0.1 mg/mL His-M195FANCF conferred resistance to mitomycin C. No similar protection was noted in CD33− parental cells or CD33+ FA cells belonging to groups A and C. These results demonstrate that antibody-directed, receptor-mediated protein transfer is a versatile method for the delivery of biologically active proteins into hematopoietic cells.
Molecular basis of the adult i phenotype and the gene responsible for the expression of the human blood group I antigen
Authors: Yu Lung-Chih , Twu Yuh-Ching , Chang Ching-Yi , Lin Marie 
Published: October 2002

AbstractThe human blood group i and I antigens are characterized as linear and branched repeats of N-acetyllactosamine, respectively. Conversion of the i to the I structure requires the activity of I-branching β-1,6-N-acetylglucosaminyltransferase (IGnT). Thus the blood group I gene is assigned to encode a β-1,6-N-acetylglucosaminyltransferase; however, its identity has not been confirmed. The null phenotype of I, the adult i phenotype, provides a means to identify the I gene. Interestingly, the adult i phenotype has been noted to be associated with congenital cataracts in Asians. Molecular genetic studies of 3 adult i pedigrees are reported here. The results obtained on mutation detection within the 2 I-branching enzyme encoding genes, segregation analyses, and enzyme function assays identify molecular changes associated with the adult i phenotype. The adult i phenotype in 2 of the pedigrees studied resulted from 1043G→A and 1148G→A mutations, which predict Gly348Glu and Arg383His alterations, respectively, in theIGnT gene. These amino acid changes abolished the original GlcNAc-transferase activity. Deletion of the IGnT gene was observed in the person with adult i phenotype in the third pedigree. These findings suggest that the IGnT gene, first reported in 1993, is the candidate for the blood group I gene. Confirmation of the blood group I gene will further assist in the investigations of the molecular genetics that control I antigen expression in secretions and the molecular basis for the association of the adult i phenotype with congenital cataracts in Asians.
Salvage therapy for multiple myeloma with thalidomide and CED chemotherapy
Authors: Moehler Thomas M. , Neben Kai , Benner Axel , Egerer Gerlinde , Krasniqi Fatime , Ho Anthony D. , Goldschmidt Hartmut 
Published: October 2002

AbstractThe feasibility and efficacy of a combination of thalidomide, cyclophosphamide, etoposide, and dexamethasone were studied in 56 patients with poor-prognosis multiple myeloma. Of 50 patients evaluable for response, 4% achieved complete response (CR), 64% partial response (PR), 18% minimal response (MR), 6% stable disease (SD), and 8% progressive disease (PD), resulting in an objective response rate (≥ MR) of 86.0% (76.7% overall objective response rate in intent-to-treat analysis; n = 56). Subsequent to successful remission induction, 18 patients received autologous or allogeneic stem cell transplantation. The median progression-free survival in all patients was 16 months. The median overall survival time could not be calculated, since the last observed death occurred after 16 months of follow-up (median follow-up of 14 months) with a corresponding estimated survival probability of 55%. Severe adverse effects (World Health Organization III/IV) included infectious complications (35.7%) and cardiovascular events (7.1%). The data suggest that Thal improves antitumor activity of salvage chemotherapy regimens in poor-prognosis multiple myeloma.
Identification and characterization of cis elements in the STAT3 gene regulating STAT3α and STAT3β messenger RNA splicing
Authors: Shao Huang , Quintero Andres J. , Tweardy David J. 
Published: October 2002

Abstract
Signal transducer and activator of transcription 3 (STAT3) is an oncogene and a critical regulator of multiple cell-fate decisions, including myeloid cell differentiation. Two isoforms of STAT3 have been identified: α (p92) and β (p83). These differ structurally in their C-terminal transactivation domains, resulting in distinct functional activities. The cis genetic elements that regulate the ratio of α to β messenger RNA (mRNA) are unknown. In this study, cloning, sequencing, and splicing analysis of the human and murine STAT3 genes revealed a highly conserved 5′ donor site for generation of both α and β mRNA and distinct branch-point sequences, polypyrimidine tracts, and 3′ acceptor sites (ASs) for each. The β 3′ AS was found to be located 50 nucleotides downstream of the α 3′ AS in exon 23. Two additional cryptic 3′ ASs (δ and ε) were also identified. Thus, we identified for the first time the cisregulatory sequences responsible for generation of STAT3α and STAT3β mRNA.
Autologous stem cell transplantation for HIV-associated lymphoma
Authors: Krishnan Amrita , Molina Arturo , Zaia John , Nademanee Auayporn , Kogut Neil , Rosenthal Joseph , Woo Doni , Forman Stephen J. 
Published: October 2002

Abstract
Is peripheral stem cell mobilization followed by autologous stem cell transplantation (ASCT) feasible in patients with human immunodeficiency virus (HIV)– associated lymphoma (HIV-L)? Studies have demonstrated that, in the HIV- negative (HIV−) setting, ASCT may improve lymphoma-free survival in high-risk non-Hodgkin lymphoma (NHL) or relapsed Hodgkin disease (HD) and NHL. Given the poor prognosis of HIV-L with conventional chemotherapy, this dose-intensive approach was explored. Nine patients with HIV-HD or NHL mobilized a median of 10.6 × 106 CD34+ cells/kg and engrafted after ASCT. CD4 counts recovered to pretransplantation levels and HIV viral loads were controlled in patients compliant with antiretroviral therapy. Seven of 9 patients remain in remission from their lymphoma at a median of 19 months after transplantation. Thus, patients with HIV-L on antiretroviral therapy can engraft following ASCT. Prolonged lymphoma remissions, without significant compromise of immune function, can be seen, suggesting that ASCT can be used in selected patients with HIV-L.
Administration of cyclosporine for 24 months compared with 6 months for prevention of chronic graft-versus-host disease: a prospective randomized clinical trial
Authors: Kansu Emin , Gooley Ted , Flowers Mary E. D. , Anasetti Claudio , Deeg H. Joachim , Nash Richard A. , Sanders Jean E. , Witherspoon Robert P. , Appelbaum Frederick R. , Storb Rainer , Martin Paul J. 
Published: October 2002

Abstract
This study compared the incidence of clinical extensive chronic graft-versus-host disease (GVHD), transplantation-related mortality, survival, and relapse-free survival among recipients randomly assigned to receive a 24-month or a 6-month course of cyclosporine prophylaxis after transplantation of allogeneic marrow from an HLA-identical sibling or alternative donor. Patients who did not have clinical manifestations of chronic GVHD on day 80 after transplantation were eligible for the study if they previously had acute GVHD or if a skin biopsy showed histologic evidence of chronic GVHD. Clinical extensive chronic GVHD developed in 35 of the 89 patients (39%) in the 24-month group and 37 of the 73 patients (51%) in the 6-month group. The hazard of developing chronic GVHD was not significantly different in the 2 groups (hazard ratio = 0.76; 95% confidence interval, 0.48-1.21; P = .25). In addition, there were no significant differences between the 2 groups in transplantation-related mortality, survival, or disease-free survival.
Anatomical and Functional Evidence for a Neural Hypothalamic-Testicular Pathway that Is Independent of the Pituitary
Authors: Lee Soon , Miselis Richard , Rivier Catherine 
Published: October 2002

AbstractTestosterone (T) secretion is classically considered to be under the primary control of pituitary LH, itself regulated by the hypothalamic peptide LH-releasing hormone. Secretagogues present in the general circulation and/or manufactured in the testis can also alter Leydig cell activity independently of the pituitary. Finally, spanchnic innervation regulates testicular LH receptors and blood flow. In the present work, we provide evidence that, in addition, there may be a neural brain-testicular circuit that regulates T release function independently of LH release. We had recently reported that the intracerebroventricular injection of IL-1β, corticotropin-releasing factor, or β-adrenergic agonists significantly interfered with the T response to human chorionic gonadotropin through mechanisms that did not involve LH. Here, we show that the injection of the transganglionic retrograde tracer pseudorabies virus into the testes caused viral staining in the spinal cord, the brain stem, and the hypothalamus. This observation indicates the presence of a neural pathway between the central nervous system and the testis. We then demonstrated that spinal cord injury significantly interfered with this staining, thus supporting the hypothesis that the proposed circuit travels through the cord. Finally, we showed that spinal cord injury completely abolished the ability of intracerebroventricularly injected IL-1β or corticotropin-releasing factor to blunt the T response to human chorionic gonadotropin, which suggests that these two secretagogues act within the brain to stimulate a neural pathway that interferes with Leydig cell function independently of the pituitary. The hitherto unsuspected brain-testicular circuit that these experiments have uncovered may play a role in pathologies, so far unexplained, that are characterized by decreased T levels despite normal LH production.
Externalization of Annexin I from A Folliculo-Stellate-Like Cell Line
Authors: Chapman Lee , Nishimura Aya , Buckingham Julia C. , Morris John F. , Christian Helen C. 
Published: October 2002

AbstractOur recent studies on rat pituitary tissue suggest that the annexin I-dependent inhibitory actions of glucocorticoids may not be exerted directly on endocrine cells but indirectly via folliculo-stellate (FS) cells. FS cells contain glucocorticoid receptors and abundant annexin I. We have studied the localization of annexin I in FS cells and the ability of dexamethasone to induce annexin I secretion by an FS (TtT/GF) cell line, using Western blotting and immunofluorescence microscopy. Exposure of TtT/GF cells to dexamethasone (0.1 μm, 3 h) caused an increase in the amount of annexin I protein in the intracellular compartment and attached to the surface of the cells. In nonpermeabilized cells, immunofluorescence labeling revealed that annexin I immunoreactivity was associated with the cell surface and concentrated in focal patches on the ends of cytoplasmic processes; dexamethasone (0.1 μm, 3 h) increased both the number and intensity of these foci. Immunogold electron microscopy confirmed in anterior pituitary tissue the presence of immunoreactive-annexin at the surface of FS cell processes contacting endocrine cells. These data support our hypothesis that annexin I is released by FS cells in response to glucocorticoids to mediate glucocorticoid inhibitory actions on pituitary hormone release via a juxtacrine mechanism.
Prolonged Retention after Aggregation into Secretory Granules of Human R183H-Growth Hormone (GH), a Mutant that Causes Autosomal Dominant GH Deficiency Type II
Authors: Zhu Yong Lian , Conway-Campbell Becky , Waters Michael J. , Dannies Priscilla S. 
Published: October 2002

AbstractHuman R183H-GH causes autosomal dominant GH deficiency type II. Because we show here that the mutant hormone is fully bioactive, we have sought to locate an impairment in its progress through the secretory pathway as assessed by pulse chase experiments. Newly synthesized wild-type and R183H-GH were stable when expressed transiently in AtT20 cells, and both formed equivalent amounts of Lubrol-insoluble aggregates within 40 min after synthesis. There was no evidence for intermolecular disulfide bond formation in aggregates of wild-type hormone or the R183H mutant. Both wild-type and R183H-GH were packaged into secretory granules, assessed by the ability of 1 mm BaCl2 to stimulate release and by immunocytochemistry. The mutant differed from wild-type hormone in its retention in the cells after packaging into secretory granules; 50% more R183H-GH than wild-type aggregates were retained in AtT20 cells 120 min after synthesis, and stimulated release of R183H-GH or a mixture of R183H-GH and wild-type that had been retained in the cell was reduced. The longer retention of R183H-GH aggregates indicates that a single point mutation in a protein contained in secretory granules affects the rate of secretory granule release.
Immunocytochemical Localization of Vasopressin V1a Receptors in the Rat Pituitary Gonadotropes
Authors: Orcel Hélène , Tobin Vicky A. , Alonso Gérard , Rabié Alain 
Published: October 2002

Abstract
Immunocytochemical labeling using a specific antibody against vasopressin V1a receptor allowed the localization of this receptor within a subset of cells from male rat anterior pituitary. The presence of transcripts of the corresponding gene in the anterior pituitary was confirmed by RT-PCR. Multiple immunocytochemical labeling combined with confocal microscopy allowed the identification of the V1a-labeled cells as gonadotropes. At the subcellular level, the vasopressin V1a receptor was mainly associated with cytoplasmic vesicles dispersed throughout the cell, which were not the secretory granules storing LH or FSH. In addition to effects exerted by vasopressin via central targets involved in the reproductive pathways, the presence of vasopressin V1a receptors on gonadotropes supports the controversial hypothesis of a local direct action of the neuropeptide on this cell type.
Unexpected Deposition of Brown Fat in Mammary Gland During Postnatal Development
Authors: Gouon-Evans Valérie , Pollard Jeffrey W. 
Published: October 2002

AbstractMammary fat tissue is crucial for mammary ductal morphogenesis in both fetal and adult mice. There are two kinds of adipocytes, the energy-storing white and the energy-dissipating brown adipocyte. The precise identity of the types of adipocyte in the mammary gland has never been investigated but was always assumed to be only white fat. In this study, we show that both white and brown adipocytes are present in the postnatal mammary gland. The amount of brown adipose tissue (BAT) examined by histology and electron microscopy correlates with the transcript levels of uncoupling protein 1, which is a mitochondrial carrier expressed exclusively in BAT. Uncoupling protein 1 mRNAs are the highest during prepuberty, decrease upon puberty, and are finally undetectable in the adult mammary gland. The analysis of a BAT-depleted mouse model showed that depletion of mammary BAT in early postnatal development induces epithelial differentiation. Alveolar structures were formed along all ducts and were functional since they produced β-casein. However, mammary transplantation experiments indicated that a systemic effect was responsible for epithelium differentiation. Our data suggest that BAT negatively regulates the differentiation of mammary epithelial cells in a systemic manner during prepubertal ductal outgrowth.