bluuebunny/crossref_metadata_2025_split huggingface dataset:
CD137 stimulation delivers an antigen-independent growth signal for T lymphocytes with memory phenotype
Authors: Zhu Yuwen , Zhu Gefeng , Luo Liqun , Flies Andrew S. , Chen Lieping 
Published: January 2007

AbstractCD137 has long been recognized as a costimulatory receptor for growth and functional maturation of recently activated T cells in the presence of T-cell receptor signal. In this report, we present the fact that, in the absence of MHC and antigen, triggering of CD137 by an agonist monoclonal antibody induces vigorous growth of both CD8+ and CD4+ T cells with memory phenotype, whereas it does not affect naive T cells. Moreover, T cells with memory phenotype accumulate progressively in transgenic mice overexpressing CD137 ligand. CD137-mediated proliferation of memory T cells is directly through CD137 on T cells and does not require IL-15 and IFN-γ. Our results define a new role of CD137 signal in the growth of memory T cells.
B-cell development fails in the absence of the Pbx1 proto-oncogene
Authors: Sanyal Mrinmoy , Tung James W. , Karsunky Holger , Zeng Hong , Selleri Licia , Weissman Irving L. , Herzenberg Leonore A. , Cleary Michael L. 
Published: January 2007

AbstractPbx1, a homeodomain transcription factor that was originally identified as the product of a proto-oncogene in acute pre-B–cell leukemia, is a global regulator of embryonic development. However, embryonic lethality in its absence has prevented an assessment of its role in B-cell development. Here, using Rag1-deficient blastocyst complementation assays, we demonstrate that Pbx1 null embryonic stem (ES) cells fail to generate common lymphoid progenitors (CLPs) resulting in a complete lack of B and NK cells, and a partial impairment of T-cell development in chimeric mice. A critical role for Pbx1 was confirmed by rescue of B-cell development from CLPs following restoration of its expression in Pbx1-deficient ES cells. In adoptive transfer experiments, B-cell development from Pbx1-deficient fetal liver cells was also severely compromised, but not erased, since transient B lymphopoiesis was detected in Rag-deficient recipients. Conditional inactivation of Pbx1 in pro-B (CD19+) cells and thereafter revealed that Pbx1 is not necessary for B-cell development to proceed from the pro-B–cell stage. Thus, Pbx1 critically functions at a stage between hematopoietic stem cell development and B-cell commitment and, therefore, is one of the earliest-acting transcription factors that regulate de novo B-lineage lymphopoiesis.
NB1 mediates surface expression of the ANCA antigen proteinase 3 on human neutrophils
Authors: von Vietinghoff Sibylle , Tunnemann Gisela , Eulenberg Claudia , Wellner Maren , Cristina Cardoso M. , Luft Friedrich C. , Kettritz Ralph 
Published: January 2007

AbstractAntineutrophil cytoplasmic antibodies (ANCAs) with specificity for proteinase 3 (PR3) are central to a form of ANCA-associated vasculitis. Membrane PR3 (mPR3) is expressed only on a subset of neutrophils. The aim of this study was to determine the mechanism of PR3 surface expression on human neutrophils. Neutrophils were isolated from patients and healthy controls, and hematopoietic stem cells from cord blood served as a model of neutrophil differentiation. Surface expression was analyzed by flow cytometry and confocal microscopy, and proteins were analyzed by Western blot experiments. Neutrophil subsets were separated by magnetic cell sorting. Transfection experiments were carried out in HEK293 and HL60 cell lines. Using neutrophils from healthy donors, patients with vasculitis, and neutrophilic differentiated stem cells we found that mPR3 display was restricted to cells expressing neutrophil glycoprotein NB1, a glycosylphosphatidylinositol (GPI)–linked surface receptor. mPR3 expression was decreased by enzymatic removal of GPI anchors from cell membranes and was absent in a patient with paroxysmal nocturnal hemoglobinuria. PR3 and NB1 coimmunoprecipitated from and colocalized on the neutrophil plasma membrane. Transfection with NB1 resulted in specific PR3 surface binding in different cell types. We conclude that PR3 membrane expression on neutrophils is mediated by the NB1 receptor.
Rapid infusion rituximab in combination with corticosteroid-containing chemotherapy or as maintenance therapy is well tolerated and can safely be delivered in the community setting
Authors: Sehn Laurie H. , Donaldson Jane , Filewich Allison , Fitzgerald Catherine , Gill Karamjit K. , Runzer Nancy , Searle Barb , Souliere Sheila , Spinelli John J. , Sutherland Judy , Connors Joseph M. 
Published: January 2007

AbstractThe increasing usage of rituximab in the management of non-Hodgkin lymphoma (NHL) has created huge logistical challenges with respect to the delivery of this time- and labor-intensive drug. To address these challenges, we developed and tested the feasibility of a 90-minute infusion schedule for rituximab (20% of the dose administered in the first 30 minutes, remaining 80% administered over 60 minutes). A safety analysis performed in 150 patients receiving rituximab with corticosteroid-containing chemotherapy and 56 patients receiving rituximab as maintenance therapy demonstrated that this schedule was well tolerated, with no grade 3 or 4 infusion reactions observed. In addition, no increase in minor reactions was noted. More than 1200 patients have been treated with this rapid rituximab infusion schedule in the province of British Columbia (BC), demonstrating its safety in the community setting. The adoption of this 90-minute schedule as standard practice has had a positive impact on resource utilization.
Insulin Resistance Increases the Risk of Spontaneous Abortion after Assisted Reproduction Technology Treatment
Authors: Tian Li , Shen Huan , Lu Qun , Norman Robert J. , Wang Jim 
Published: January 2007

Abstract
Objective: This study aims to examine the impact of insulin resistance (IR) on the risk of spontaneous abortion in patients who received infertility treatment.
Patients and Methods: This is a cohort study of 107 patients who achieved their first pregnancy after infertility treatment in a tertiary medical center. A homeostasis model assessment of IR (HOMA-IR) was carried out. Patient demographic characteristics and pregnancy outcome were also recorded. Statistical comparison was made between patients with and without IR. Logistical regression analysis was used to assess the effect of IR and several other factors simultaneously on the risk of spontaneous abortion.
Results: The incidence of spontaneous abortion was 17.8%. The association of IR with the risk of spontaneous abortion was significant after adjusting for other risk factors. The effect of overweight/obesity and polycystic ovarian syndrome was not statistically significant in the multivariate model.
Discussion and Conclusion: This study suggested that IR was an independent risk factor for spontaneous abortion. Because of the high prevalence of IR in obese or polycystic ovarian syndrome patients, the risk of spontaneous abortion in these patients can be raised. Patients with IR should be advised to improve their insulin sensitivity through lifestyle change or medical intervention before infertility treatment to reduce their risk of spontaneous abortion.
Thyroglobulin Gene Mutations Producing Defective Intracellular Transport of Thyroglobulin Are Associated with Increased Thyroidal Type 2 Iodothyronine Deiodinase Activity
Authors: Kanou Yasuhiko , Hishinuma Akira , Tsunekawa Katsuhiko , Seki Koji , Mizuno Yutaka , Fujisawa Haruki , Imai Tsuneo , Miura Yoshitaka , Nagasaka Tetsuro , Yamada Chizumi , Ieiri Tamio , Murakami Masami , Murata Yoshiharu 
Published: January 2007

Abstract
Context: Most patients with defective synthesis and/or secretion of thyroglobulin (Tg) present relatively high serum free T3 (FT3) concentrations with disproportionately low free T4 (FT4) resulting in a high FT3/FT4 ratio. The mechanism of this change in FT3/FT4 ratio remains unknown.
Objective: We hypothesize that increased type 2 iodothyronine deiodinase (D2) activity in the thyroid gland may explain the higher FT3/FT4 ratio that is frequently observed in patients with abnormal Tg synthesis.
Design: We recently identified a compound heterozygous patient (patient A) with a Tg G2356R mutation and one previously described (C1245R) that is known to cause a defect in intracellular transport of Tg. In the current study, after determining the abnormality caused by G2356R, we measured D2 activity as well as its mRNA level in the thyroid gland. We also measured the thyroidal D2 activity in three patients with Tg transport defect and in normal thyroid tissue.
Results: Morphological and biochemical analysis of the thyroid gland from patient A, complemented by a pulse-chase experiment, revealed that G2356R produces a defect in intracellular Tg transport. D2 activity but not type 1 deiodinase in thyroid glands of patients with abnormal Tg transport was significantly higher than in normal thyroid glands, whereas D2 mRNA level in patient A was comparable with that in normal thyroid glands. Furthermore, there was a positive correlation between D2 activity and FT3/FT4 ratios.
Conclusion: Increased thyroidal D2 activity in the thyroid gland is responsible for the higher FT3/FT4 ratios in patients with defective intracellular Tg transport.
Relationship between Vascular Reactivity and Lipids in Mexican-Americans with Type 2 Diabetes Treated with Pioglitazone
Authors: Wajcberg Estela , Sriwijitkamol Apiradee , Musi Nicolas , DeFronzo Ralph A. , Cersosimo Eugenio 
Published: January 2007

Abstract
Context: Vascular dysfunction and insulin resistance precede atherosclerosis in type 2 diabetes (T2DM). Better knowledge of the interaction between these is of considerable clinical interest.
Objective: The objective of this study was to examine the association between inflammation, glucose, and lipid metabolism and vascular dysfunction.
Design and Setting: We conducted a randomized, double-blind, controlled trial of pioglitazone vs. placebo and other therapies aimed at equal glycemic control for 24 wk at an academic tertiary referral clinic.
Patients and Interventions: Mexican-American subjects with T2DM and no complications were randomly assigned to pioglitazone 45 mg daily (PIO, n = 16) or placebo (CON, n = 15) and matched for age, gender, body mass index, diabetes duration, and glycemic control. All subjects completed the study.
Main Outcome Measure: We looked for improved vascular reactivity independent of glycemic control but closely related to plasma adiponectin, lipids, and insulin sensitivity.
Results: After 24 wk, there was an equal decrease in fasting plasma glucose (∼135 mg/dl), glycosylated hemoglobin (∼7.0%), and glucose production (∼15%). The decrease in free fatty acids (30 vs. 10%) and increase in glucose disposal (40 vs. 25%) were greater in PIO vs. CON (P &lt; 0.05). In PIO, plasma high-density lipoprotein rose by 15% (P &lt; 0.05), and low-density lipoprotein and high-density lipoprotein particle size rose significantly (P &lt; 0.01). Plasma adiponectin doubled in PIO (from 6.1 ± 0.8 to 12.7 ± 2.1 μg/ml). Forearm blood flow rose equally (∼130%) during reactive hyperemia in both groups, although after therapy, the increase was greater (P &lt; 0.001) in PIO (153%) than in CON (137%); vasodilation was greater (P = 0.01) in PIO (92, 160, and 204%) than in CON with acetylcholine (74, 130, and 144%) and with sodium nitroprusside (PIO = 164 and 253% vs. 116 and 230%; P = 0.04). The elevation in diameter was also greater in PIO (13 vs. 10%; P &lt; 0.05). Vascular responses correlated with plasma free fatty acids, adiponectin, and low-density lipoprotein particle size but not with glycemic control.
Conclusion: These data indicate that pioglitazone improves vascular reactivity irrespective of glycemic control and suggest a close association with changes in fat cell metabolism.
Increased Adiposity Enhances Intrafollicular Estradiol Levels in Normoandrogenic Ovulatory Women Receiving Gonadotropin-Releasing Hormone Analog/Recombinant Human Follicle-Stimulating Hormone Therapy for in Vitro Fertilization
Authors: Dumesic Daniel A. , Lesnick Timothy G. , Abbott David H. 
Published: January 2007

Abstract
Context: Body mass index (BMI) reflects the amount of insulin in the human follicle and may enhance insulin action as a cogonadotropin.
Objective: This study examined whether increased adiposity enhances intrafollicular steroidogenesis in normoandrogenic ovulatory women receiving GnRH analog/recombinant human FSH therapy for in vitro fertilization.
Design, Setting, and Participants: Study participants were from an institutional practice and comprised 30 normoandrogenic ovulatory women who were lean (n = 17; BMI &lt; 25 kg/m2) or overweight (n = 13; BMI ≥ 25 kg/m2). Women received GnRH analog after basal serum hormone determinations and oral glucose tolerance testing, followed by recombinant human FSH therapy and human chorionic gonadotropin administration when two or more follicles 18 mm or larger in diameter were present.
Intervention: Follicle fluid was aspirated at oocyte retrieval from the first follicle of each ovary.
Main Outcome Measures: Follicle fluid was assayed for estradiol (E2), progesterone, 17-hydroxyprogesterone, androstenedione, testosterone, dihydrotestosterone, insulin, glucose, and lactate.
Results: Overweight women had hyperinsulinemia (P = 0.03) with decreased serum SHBG (P = 0.001) and increased serum free testosterone levels (P = 0.02). Elevated intrafollicular insulin levels in overweight women (P = 0.004) were accompanied by normal glucose and lactate levels. Intrafollicular E2 levels were greater in overweight vs. lean women (P = 0.03), whereas the remaining intrafollicular steroid levels were similar in both female groups.
Conclusion: In normoandrogenic ovulatory women undergoing in vitro fertilization, increased adiposity elevates insulin and E2 levels in terminally differentiated follicles without altering intrafollicular androgen levels or luteinization. Additional studies are required to determine whether these abnormalities impair oocyte development.
RbAp48 is a Target of Nuclear Factor-κB Activity in Thyroid Cancer
Authors: Pacifico Francesco , Paolillo Michele , Chiappetta Gennaro , Crescenzi Elvira , Arena Simona , Scaloni Andrea , Monaco Mario , Vascotto Carlo , Tell Gianluca , Formisano Silvestro , Leonardi Antonio 
Published: January 2007

Abstract
Context: We have recently shown that nuclear factor (NF)-κB activity is constitutively elevated in anaplastic human thyroid carcinomas. The inhibition of NF-κB in the anaplastic thyroid carcinoma cell line (FRO) leads to increased susceptibility to apoptosis induced by chemotherapeutic drugs and to the block of oncogenic activity.
Objectives: To understand better the molecular mechanisms played by NF-κB in thyroid oncogenesis, we performed a differential proteomic analysis between FRO transfected with a superrepressor form of inhibitor of κBα (IκBαM) and the parental counterpart (FRO Neo cells).
Results: Differential proteomic analysis revealed that the retinoblastoma-associated protein 48 (RbAp48) is down-regulated in the absence of functional NF-κB. Immunohistochemical analysis of normal and pathological human thyroid specimens confirmed that RbAp48 is strongly overexpressed in primary human carcinomas. Reduction of RbAp48 expression using small interfering RNA determined the suppression of tumorigenicity, very likely due to the decrease of their growth rate rather than to an increased susceptibility to apoptosis. In addition, we showed that NF-κB, at least in part, transcriptionally controls RbAp 48. A functional NF-κB consensus sequence was located within the promoter region of RbAp48 human gene, and embryonic fibroblasts isolated from the p65 knockout mouse (murine embryonic fibroblasts p65−/−) showed decreased expression of RbAp48.
Conclusion: Our results show that RbAp48 is a NF-κB-regulated gene playing an important role in thyroid cancer cell autonomous proliferation.
Transcriptional Profiling of Androgen Receptor (AR) Mutants Suggests Instructive and Permissive Roles of AR Signaling in Germ Cell Development
Authors: Eacker Stephen M. , Shima James E. , Connolly Charles M. , Sharma Manju , Holdcraft Robert W. , Griswold Michael D. , Braun Robert E. 
Published: January 2007

AbstractThe androgen receptor (AR) is a transcription factor that plays a critical role in male sexual development, spermatogenesis, and maintenance of hormonal homeostasis. Despite the extensive knowledge of the phenotypic consequences of mutations in Ar, very little is known about the transcriptional targets of AR within the testis. To identify potential targets of androgen signaling in the testis, we have analyzed the transcriptional profile of adult testes from Ar hypomorphs alone or in combination with Sertoli cell-specific Ar ablation. Using Affymetrix MOE430A mouse genome arrays we interrogated more than 22,000 transcripts. We found the expression level of 62 transcripts in the Ar mutants differed by greater than 2-fold compared with wild type. We also found that more transcripts were up-regulated than down-regulated, highlighting AR’s role as a transcriptional repressor in the testis. Twelve transcripts were uniquely affected, and 16 transcripts were more severely affected in Sertoli cell-specific Ar ablation compared with hypomorphic Ar mutants. Using a comparative genomic approach, we analyzed the 6 kb around the transcriptional start sites of affected transcripts for conserved AREs (androgen response elements). We identified at least one conserved ARE in 65% of the genes misregulated in our microarray analysis where clear mouse-human orthologs were available. We used a reporter assay in cell culture to functionally verify the AREs for the kallikrein 27 gene. This suggests that the majority of the misregulated transcripts have a high probability of being direct AR targets. The transcripts affected by these Ar mutations encode a diverse array of proteins whose molecular functions support the contention that AR supports spermatogenesis in both a permissive and instructive fashion.
Essential Role of GATA2 in the Negative Regulation of Thyrotropin β Gene by Thyroid Hormone and Its Receptors
Authors: Matsushita Akio , Sasaki Shigekazu , Kashiwabara Yumiko , Nagayama Koji , Ohba Kenji , Iwaki Hiroyuki , Misawa Hiroko , Ishizuka Keiko , Nakamura Hirotoshi 
Published: January 2007

AbstractPreviously we reported that the negative regulation of the TSHβ gene by T3 and its receptor [thyroid hormone receptor (TR)] is observed in CV1 cells when GATA2 and Pit1 are introduced. Using this system, we further studied the mechanism of TSHβ inhibition. The negative regulatory element (NRE), which had been reported to mediate T3-bound TR (T3-TR)-dependent inhibition, is dispensable, because deletion or mutation of NRE did not impair suppression. The reporter construct, TSHβ-D4-chloramphenicol acetyltransferase, which possesses only the binding sites for Pit1 and GATA2, was activated by GATA2 alone, and this transactivation was specifically inhibited by T3-TR. The Zn finger region of GATA2 interacts with the DNA-binding domain of TR in a T3-independent manner. The suppression by T3-TR was impaired by overexpression of a dominant-negative type TR-associated protein (TRAP) 220, an N- and C-terminal deletion construct, indicating the participation of TRAP220. Chromatin immunoprecipitation assays with a thyrotroph cell line, TαT1, revealed that T3 treatment recruited histone deacetylase 3, reduced the acetylation of histone H4, and caused the dissociation of TRAP220 within 15–30 min. The reduction of histone H4 acetylation was transient, whereas the dissociation of TRAP220 persisted for a longer period. In the negative regulation of the TSHβ gene by T3-TR we report that 1) GATA2 is the major transcriptional activator of the TSHβ gene, 2) the putative NRE previously reported is not required, 3) TR-DNA-binding domain directly interacts with the Zn finger region of GATA2, and 4) histone deacetylation and TRAP220 dissociation are important.
Maximal Activity of the Luteinizing Hormoneβ-Subunit Gene Requires β-Catenin
Authors: Salisbury Travis B. , Binder April K. , Grammer Jean C. , Nilson John H. 
Published: January 2007

AbstractGnRH regulates expression of LHB via transcriptional regulation of early growth response 1 (EGR1), an immediate early gene that encodes a zinc-finger DNA-binding protein. EGR1 interacts functionally with the orphan nuclear receptor steroidogenic factor 1 (SF1) and pituitary homeobox 1, a member of the paired-like homeodomain family. The functional synergism of this tripartite interaction defines the maximal level of LHB transcription that can occur in response to GnRH. Results presented herein provide new evidence that the interaction between SF1 and EGR1 also requires β-catenin, a transcriptional coactivator and member of the canonical Wnt signaling pathway. For instance, targeted reduction of β-catenin attenuates activity of a GnRH-primed LHB promoter. Additional gene reporter assays indicate that overexpression of β-catenin, or its targeted reduction by small interfering RNA, modulates activity of both SF1 and EGR1 as well as their functional interaction. β-Catenin coimmunoprecipitates with SF1. Moreover, an SF1 mutant that lacks a β-catenin binding domain has compromised transcriptional activity and fails to interact synergistically with EGR1. Finally, GnRH promotes β-catenin colocalization with SF1 and EGR1 on the endogenous mouse Lhb promoter-regulatory region. Taken together, these data suggest that β-catenin binds to SF1 and that this interaction is required for subsequent functional interaction with EGR1. Thus, these data identify β-catenin as a new and required member of the basal transcriptional complex that allows the LHB promoter to achieve maximal activity in response to GnRH.