bluuebunny/crossref_metadata_2025_split huggingface dataset:
NF-Y cooperates with USF1/2 to induce the hematopoietic expression of HOXB4
Authors: Zhu Jiang , Giannola Diane M. , Zhang Yi , Rivera Adam J. , Emerson Stephen G. 
Published: June 2003

AbstractThe transcription factor homeobox B4 (HOXB4) is preferentially expressed in immature hematopoietic cells and implicated in the transition from primitive hematopoiesis to definitive hematopoiesis as well as in immature hematopoietic cell proliferation and differentiation. We previously identified Hox response element 1 (HxRE-1) and HxRE-2/E-box as 2 critical DNA-binding sites of the HOXB4 promoter active in hematopoietic cells and demonstrated that upstream stimulating factor 1 and 2 (USF1/2) activate HOXB4 transcription through their binding to the E-box site. Here we report that the trimeric regulatory complex nuclear factor Y (NF-Y) is the factor that recognizes HxRE-1 and activates the HOXB4 promoter in hematopoietic cells. We further show that NF-Y interacts biochemically with USF1/2 on the HOXB4 promoter, and that the formation of this NF-Y/USF1/2 complex is required for the full activity of the HOXB4 promoter. Most important, NF-Ya subunit protein levels are found to be lower in c-Kit-Gr-1+ granulocytic bone marrow (BM) cells than in c-Kit+ immature BM cells, in parallel with a reduction of NF-Y occupancy on the HOXB4 promoter as shown by chromatin immunoprecipitation (ChIP) assay. These results suggest that NF-Y is a developmentally regulated inducer of the HOXB4 gene in hematopoietic cells. (Blood. 2003;102:2420-2427)
Polymorphic variation in GSTP1 modulates outcome following therapy for multiple myeloma
Authors: Dasgupta Ranjit K. , Adamson Peter J. , Davies Faith E. , Rollinson Sara , Roddam Philippa L. , Ashcroft A. John , Dring Ann M. , Fenton James A. L. , Child J. Anthony , Allan James M. , Morgan Gareth J. 
Published: June 2003

Abstract
Glutathione S-transferase P1 (GSTP1) is a phase 2 drug metabolism enzyme involved in the metabolism and detoxification of a range of chemotherapeutic agents. A single nucleotide polymorphism (Ile105Val) results in a variant enzyme with lower thermal stability and altered catalytic activity. We hypothesized that patients with the less stable variant have a decreased ability to detoxify chemotherapeutic substrates, including melphalan, and have an altered outcome following treatment for multiple myeloma. We have assessed the impact of GSTP1 codon 105 polymorphisms in 222 patients entered into the Medical Research Council (MRC) myeloma VII trial (comparing standard-dose chemotherapy with high-dose therapy). In the standard-dose arm, patients with the variant allele (105Val) had an improved progression-free survival (PFS) (adjusted hazard ratios for PFS were 0.55 for heterozygotes and 0.52 for 105Val homozygotes, compared with 105Ile homozygotes; P for trend = .04); this was supported by a trend to improved overall survival, greater likelihood of entering plateau and shorter time to reach plateau in patients with the 105Val allele. No difference in outcome by genotype was found for patients treated with high-dose therapy. However, the progression-free survival advantage of the high-dose arm was seen only in patients homozygous for 105Ile (P = .008). (Blood. 2003;102:2345-2350)
HLA-matched unrelated donor hematopoietic cell transplantation after nonmyeloablative conditioning for patients with hematologic malignancies
Authors: Maris Michael B. , Niederwieser Dietger , Sandmaier Brenda M. , Storer Barry , Stuart Monic , Maloney David , Petersdorf Effie , McSweeney Peter , Pulsipher Michael , Woolfrey Ann , Chauncey Thomas , Agura Ed , Heimfeld Shelly , Slattery John , Hegenbart Ute , Anasetti Claudio , Blume Karl , Storb Rainer 
Published: June 2003

Abstract
A hematopoietic cell transplantation (HCT) approach was developed for elderly or ill patients with hematologic malignancies that employed nonmyeloablative conditioning to avoid common regimen-related toxicities and relied on graft-versus-tumor effects for control of malignancy. Eighty-nine patients, median age 53 years, were given fludarabine (90 mg/m2) and 2 Gy total body irradiation. Marrow (n = 18) or granulocyte colony-stimulating factor (G-CSF)–stimulated peripheral blood mononuclear cells (G-PBMCs; n = 71) were transplanted from unrelated donors matched for human leukocyte antigen A (HLA-A), -B, -C antigens and -DRB1 and -DQB1 alleles. Postgrafting immunosuppression included mycophenolate mofetil and cyclosporine. Donor T-cell chimerism was higher for G-PBMCs compared with marrow recipients. Durable engraftment was observed in 85% of G-PBMCs and 56% of marrow recipients. Cumulative probabilities of grade II, III, and IV acute graft-versus-host disease (GVHD) were 42%, 8%, and 2%, respectively. Nonrelapse mortality at day 100 and at 1 year was 11% and 16%, respectively. One-year overall survivals and progression-free survivals were 52% and 38%, respectively. G-PBMC recipients had improved survival (57% vs 33%) and progression-free survival (44% vs 17%) compared with marrow recipients. HLA-matched unrelated donor HCT after nonmyeloablative conditioning is feasible in patients ineligible for conventional HCT. G-PBMCs conferred higher donor T-cell chimerism, greater durable engraftment, and better progression-free and overall survivals compared with marrow.
Preclinical in vivo evaluation of pseudotyped adeno-associated virus vectors for liver gene therapy
Authors: Grimm Dirk , Zhou Shangzhen , Nakai Hiroyuki , Thomas Clare E. , Storm Theresa A. , Fuess Sally , Matsushita Takashi , Allen James , Surosky Richard , Lochrie Michael , Meuse Leonard , McClelland Alan , Colosi Peter , Kay Mark A. 
Published: June 2003

Abstract
We report the generation and use of pseudotyped adeno-associated viral (AAV) vectors for the liver-specific expression of human blood coagulation factor IX (hFIX). Therefore, an AAV-2 genome encoding the hfIX gene was cross-packaged into capsids of AAV types 1 to 6 using efficient, large-scale technology for particle production and purification. In immunocompetent mice, the resultant vector particles expressed high hFIX levels ranging from 36% (AAV-4) to more than 2000% of normal (AAV-1, -2, and -6), which would exceed curative levels in patients with hemophilia. Expression was dose- and time-dependent, with AAV-6 directing the fastest and strongest onset of hFIX expression at all doses. Interestingly, systemic administration of 2 × 1012 vector particles of AAV-1, -4, or -6 resulted in hFIX levels similar to those achieved by portal vein delivery. For all other serotypes and particle doses, hepatic vector administration yielded up to 84-fold more hFIX protein than tail vein delivery, corroborated by similarly increased vector DNA copy numbers in the liver, and elicited a reduced immune response against the viral capsids. Finally, neutralization assays showed variable immunologic cross-reactions between most of the AAV serotypes. Our technology and findings should facilitate the development of AAV pseudotype-based gene therapies for hemophilia B and other liver-related diseases. (Blood. 2003;102:2412-2419)
The homeoprotein Hex is required for hemangioblast differentiation
Authors: Guo Ying , Chan Rebecca , Ramsey Heather , Li Weiming , Xie Xiaodong , Shelley William C. , Martinez-Barbera Juan Pedro , Bort Bernardo , Zaret Kenneth , Yoder Mervin , Hromas Robert 
Published: June 2003

AbstractThe first hematopoietic and endothelial progenitors are derived from a common embryonic precursor termed the hemangioblast. The genetic cascades that regulate the differentiation of the hemangioblast to hematopoietic and endothelial cells are largely unknown. In general, much of embryonic development is coordinately regulated by temporal and spatial expression of transcription factors, such as the Homeobox (Hox) gene family. We and others isolated a divergent homeobox gene termed Hex (or Prh) that is preferentially expressed in hematopoietic and endothelial cells. Using in vitro Hex-/- embryonic stem (ES) cell differentiation, in vivo yolk sac hematopoietic progenitor assays, and chimeric mouse analysis, we found that Hex is required for differentiation of the hemangioblast to definitive embryonic hematopoietic progenitors and to a lesser extent endothelial cells. Therefore, Hex is a novel regulator of hemangioblast differentiation to hematopoietic and endothelial cells. (Blood. 2003;102:2428-2435)
Sex-specific alterations in neutrophil apoptosis: the role of estradiol and progesterone
Authors: Molloy Eleanor J. , O'Neill Amanda J. , Grantham Julie J. , Sheridan-Pereira Margaret , Fitzpatrick John M. , Webb David W. , Watson R. William G. 
Published: June 2003

AbstractWomen are conferred with greater immunologic and survival benefits compared to men. Female sex steroids contribute to this sexual dimorphism. Furthermore, during human pregnancy when female sex hormones are elevated, neutrophil apoptosis is delayed. This study examines the specific effects of estradiol and progesterone on neutrophil apoptosis and function in healthy adult men and women. We also examined the contribution of these hormones to the persistence and resolution of an inflammatory response. Spontaneous apoptosis was significantly decreased in women compared with men. Physiologic doses of estradiol and progesterone caused a further delay in spontaneous apoptosis in both men and women but did not diminish Fas antibody-induced apoptosis. The delay in apoptosis was mediated at the level of the mitochondria with decreased release of cytochrome c, which may alter caspase cleavage and activity. There were no associated alterations in neutrophil CD11b, but production of reactive oxygen intermediates (ROIs) in women was increased. Thus, female sex hormones mediate delayed neutrophil apoptosis in both sexes and enhance female intracellular production of ROIs. Modulating hormonal responses may be an effective therapeutic tool in combating inflammatory diseases. (Blood. 2003;102:2653-2659)
Phase 2 clinical and pharmacologic study of clofarabine in patients with refractory or relapsed acute leukemia
Authors: Kantarjian Hagop , Gandhi Varsha , Cortes Jorge , Verstovsek Srdan , Du Min , Garcia-Manero Guillermo , Giles Francis , Faderl Stefan , O'Brien Susan , Jeha Sima , Davis Jan , Shaked Zeev , Craig Adam , Keating Michael , Plunkett William , Freireich Emil J 
Published: June 2003

Abstract
In a phase 2 study, 62 patients with relapsed and refractory acute myeloid leukemia (AML; n = 31), myelodysplastic syndrome (MDS; n = 8), chronic myeloid leukemia in blastic phase (CMLBP; n = 11), and acute lymphocytic leukemia (ALL; n = 12) received 40 mg/m2 clofarabine intravenously over 1 hour daily for 5 days, every 3 to 6 weeks. Twenty patients (32%) achieved complete response (CR), 1 had a partial response (PR), and 9 (15%) achieved CR but without platelet recovery (CRp), for an overall response rate of 48%. In AML, responses were noted in 2 (18%) of 11 patients in first salvage with short first CR (≤ 12 months), in 7 (87%) of 8 patients with longer first CR, and in 8 (67%) of 12 patients in second or subsequent salvage. Responses were observed in 4 of 8 patients with high-risk MDS (50%), in 7 (64%) of 11 with CML-BP, and in 2 (17%) of 12 with ALL. Severe reversible liver dysfunction was noted in 15% to 25%. After the first clofarabine infusion, responders accumulated more clofarabine triphosphate in blasts compared with nonresponders (median 18 vs 10 μM; P = .03). This increased only in responders (median, 1.8-fold; P = .008) after the second clofarabine infusion. In summary, clofarabine is active in acute leukemias and MDS; cellular pharmacokinetics may have prognostic significance. (Blood. 2003;102:2379-2386)
Design of a National Retail Data Monitor for Public Health Surveillance
Authors: Wagner Michael M. , Robinson J. Michael , Tsui Fu-Chiang , Espino Jessi , Hogan William R. 
Published: June 2003

AbstractThe National Retail Data Monitor receives data daily from 10,000 stores, including pharmacies, that sell health care products. These stores belong to national chains that process sales data centrally and utilize Universal Product Codes and scanners to collect sales information at the cash register. The high degree of retail sales data automation enables the monitor to collect information from thousands of store locations in near to real time for use in public health surveillance. The monitor provides user interfaces that display summary sales data on timelines and maps. Algorithms monitor the data automatically on a daily basis to detect unusual patterns of sales. The project provides the resulting data and analyses, free of charge, to health departments nationwide. Future plans include continued enrollment and support of health departments, developing methods to make the service financially self-supporting, and further refinement of the data collection system to reduce the time latency of data receipt and analysis.
Inflammatory Breast Carcinoma and Noninflammatory Locally Advanced Breast Carcinoma: Distinct Clinicopathologic Entities?
Authors: Anderson William F. , Chu Kenneth C. , Chang Shine 
Published: June 2003

Purpose: Inflammatory breast carcinoma (IBC) and noninflammatory locally advanced breast carcinoma (LABC) are both associated with poor prognosis; however, whether they are distinct clinicopathologic entities remains controversial. Materials and Methods: To determine whether IBC and LABC were different, we compared tumor characteristics, prognosis, and age-specific incidence rate patterns in the Surveillance, Epidemiology, and End-Results program. An age of 50 years served as a surrogate marker for menopause. Results: Younger age at diagnosis, poorer tumor grade, and negative estrogen receptors (ERs) were more predictive of IBC (n = 2,237) than of LABC (n = 7,985). Breast carcinoma survival was worse for patients with IBC than for those with LABC (log-rank test, P < .0001). Age-specific incidence rates for IBC increased until 50 years and then flattened, whereas rates for LABC increased for all ages. When rates for LABC were stratified by estrogen receptor–positive (ERP) and –negative (ERN) expression, rates for ERP and ERN diverged; that is, rates for ERP increased with advancing age, whereas rates for ERN flattened after 50 years. When rates for IBC were stratified by ER expression, rates for both ERP and ERN flattened after 50 years of age. Conclusion: IBC and LABC seemed to be distinct biologic entities, as indicated by different prognostic factor profiles and age-specific incidence rate patterns. Rates that increased before 50 years and then stabilized, possibly indicated that premenopausal exposures had a greater effect on maintaining rates for IBC than for LABC.
Phase II Trial of Thalidomide and Carmustine for Patients With Recurrent High-Grade Gliomas
Authors: Fine Howard A. , Wen Patrick Y. , Maher Elizabeth A. , Viscosi Elene , Batchelor Tracy , Lakhani Nehal , Figg William D. , Purow Benjamin W. , Borkowf Craig B. 
Published: June 2003

Purpose: The use of thalidomide as an antiangiogenic agent has met with only limited success in the treatment of malignant gliomas. On the basis of preclinical data demonstrating synergistic antitumor activity when antiangiogenic agents are combined with cytotoxic agents, we explored the clinical activity of the combination of thalidomide and carmustine (BCNU) in patients with recurrent high-grade gliomas. Patients and Methods: Patients with a histologic diagnosis of high-grade glioma and radiographic evidence of tumor progression after standard surgery, radiation, and chemotherapy were eligible for the study. Patients received BCNU 200 mg/m2 on day 1 of every 6-week cycle, and 800 mg/d of thalidomide that was escalated to a maximal dose of 1,200 mg/d as tolerated. Results: A total of 40 patients (38 with glioblastomas, two with anaplastic gliomas) were accrued to the study. The combination of thalidomide and BCNU was well tolerated; mild myelosuppression and mild to moderate sedation were the most common side effects. The median progression-free survival (100 days) and the objective radiographic response rate (24%) for patients with glioblastoma compared favorably with data from historical controls. Conclusion: This is one of the first clinical trials to evaluate the strategy of combining a putative antiangiogenic agent with a cytotoxic agent in patients with primary brain tumors. Our data demonstrate that thalidomide in combination with BCNU is well tolerated and has antitumor activity in patients with recurrent high-grade gliomas. Although the combination seems to be more active than either agent alone, such conclusions await confirmatory trials.
Abrogation of Protein Convertase 2 Activity Results in Delayed Islet Cell Differentiation and Maturation, Increased α-Cell Proliferation, and Islet Neogenesis
Authors: Vincent M. , Guz Y. , Rozenberg M. , Webb G. , Furuta M. , Steiner D. , Teitelman G. 
Published: June 2003

AbstractTo date, the role of pancreatic hormones in pancreatic islet growth and differentiation is poorly understood. To address this issue, we examined mice with a disruption in the gene encoding prohormone convertase 2 (PC2). These mice are unable to process proglucagon, prosomatostatin, and other neuroendocrine precursors into mature hormones. Initiation of insulin (IN) expression during development was delayed in PC2 mutant mice. Cells containing IN were first detected in knockout embryos on d 15 of development, 5 d later than in wild-type littermates. However, the IN+ cells of d 15 PC2 mutant mice coexpressed glucagon, as did the first appearing β-cells of controls. In addition, lack of PC2 perturbed the pattern of expression of transcription factors presumed to be involved in the determination of the mature α-cell phenotype. Thus, in contrast to controls, α-cells of mutant mice had protracted expression of Nkx 6.1 and Pdx-1, but did not express Brn-4. Islets of adult mutant mice also contained cells coexpressing insulin and somatostatin, an immature cell type found only in islets of the wild-type strain during development. In addition to the effects on islet cell differentiation, the absence of PC2 activity resulted in a 3-fold increase in the rate of proliferation of proglucagon cells during the perinatal period. This increase contributed to the development of α-cell hyperplasia during postnatal life. Furthermore, the total β-cell volume was increased 2-fold in adult mutants compared with controls. This increase was due to islet neogenesis, as the number of islets per section was significantly higher in knockout mice compared with wild-type mice, whereas both strains had similar rates of IN cell proliferation. These results indicate that hormones processed by PC2 affected processes that regulate islet cell differentiation and maturation in embryos and adults.
Mouse Strain Susceptibility to Gonadectomy-Induced Adrenocortical Tumor Formation Correlates with the Expression of GATA-4 and Luteinizing Hormone Receptor
Authors: Bielinska Malgorzata , Parviainen Helka , Porter-Tinge Susan B. , Kiiveri Sanne , Genova Elena , Rahman Nafis , Huhtaniemi Ilpo T. , Muglia Louis J. , Heikinheimo Markku , Wilson David B. 
Published: June 2003

AbstractCertain inbred strains of mice, including DBA/2J, develop adrenocortical tumors in response to gonadectomy. Spindle-shaped cells with limited steroidogenic capacity, termed A cells, appear in the subcapsular region of the adrenal gland, followed by sex steroid-producing cells known as B cells. These changes result from unopposed gonadotropin production by the pituitary, but the adrenocortical factors involved in tumorigenesis have not been characterized. GATA-4, a transcription factor normally expressed in fetal, but not adult, adrenocortical cells, was found in neoplastic cells that proliferate in the adrenal cortex of gonadectomized DBA/2J mice. GATA-4 mRNA was detected in the adrenal glands of female mice 0.5 months after ovariectomy and reached a maximum by 4 months. Castrated male mice developed adrenocortical tumors more slowly than gonadectomized females, and the onset of GATA-4 expression in the adrenal was delayed. In situ hybridization and immunohistochemistry revealed GATA-4 mRNA and protein in A and B cells, but not in normal adrenocortical cells. mRNA encoding another factor associated with adrenocortical tumorigenesis, LH receptor (LHR), was detected in A and B cells. In addition, transcripts for P450 17α-hydroxylase/C17-C20 lyase, an enzyme essential for the production of sex steroids, and inhibin-α were found in B cells. Unilateral ovarian regeneration, a phenomenon known to occur in gonadectomized mice, was observed in a subset of DBA/2J mice undergoing complete ovariectomy. In these animals, adrenocortical tumor progression was arrested; A cells and GATA-4 expression were evident, but there was no expression of LHR or P450 17α-hydroxylase/C17-C20 lyase. Strain susceptibility to adrenocortical tumorigenesis (DBA/2J ≫ FVB/N) correlated with the expression of GATA-4 and LHR, implicating these factors in the process of adrenocortical neoplasia in response to continuous gonadotropin stimulation.
Dual Role of Src Homology Domain 2-Containing Inositol Phosphatase 2 in the Regulation of Platelet-Derived Growth Factor and Insulin-Like Growth Factor I Signaling in Rat Vascular Smooth Muscle Cells
Authors: Sasaoka Toshiyasu , Kikuchi Kosei , Wada Tsutomu , Sato Akira , Hori Hiroyuki , Murakami Shihou , Fukui Kazuhito , Ishihara Hajime , Aota Rina , Kimura Ikuko , Kobayashi Masashi 
Published: June 2003

AbstractSrc homology domain 2 (SH2)-containing inositol phosphatase 2 (SHIP2) possesses 5-phosphatase activity and an SH2 domain. The role of SHIP2 in platelet-derived growth factor (PDGF) and IGF-I signaling was studied by expressing wild-type (WT-) and a catalytically defective (ΔIP-) SHIP2 into rat aortic smooth muscle cells by adenovirus-mediated gene transfer. PDGF- and IGF-I-induced tyrosine phosphorylation of their respective receptors and phosphatidylinositol 3-kinase (PI3-kinase) activity were not affected by the expression of either WT- or ΔIP-SHIP2. SHIP2 possessed 5′-phosphatase activity to hydrolyze the PI3-kinase product phosphatidylinositol 3,4,5-trisphosphate in vivo. Akt and glycogen synthase kinase 3β are known to be downstream molecules of PI3-kinase, leading to the antiapoptotic effect. Overexpression of WT-SHIP2 inhibited PDGF- and IGF-I-induced phosphorylation of these molecules and the protective effect of poly(ADP-ribose) polymerase degradation, whereas these phosphorylations and the protective effect were enhanced by the expression of ΔIP-SHIP2, which functions in a dominant negative fashion. Regarding the Ras-MAPK pathway, PDGF- and IGF-I-induced tyrosine phosphorylation of Shc was not affected by the expression of either WT- or ΔIP-SHIP2, whereas both expressed SHIP2 associated with Shc. Importantly, PDGF and IGF-I stimulation of Shc/Grb2 binding, MAPK activation, and 5-bromo-2′-deoxyuridine incorporation were all decreased in both WT- and ΔIP-SHIP2 expression. These results indicate that SHIP2 plays a negative regulatory role in PDGF and IGF-I signaling in vascular smooth muscle cells. As the bifunctional role, our results suggest that SHIP2 regulates PDGF- and IGF-I-mediated signaling downstream of PI3-kinase, leading to the antiapoptotic effect via 5-phosphatase activity, and that SHIP2 regulates the growth factor-induced Ras-MAPK pathway mainly via the SH2 domain.