bluuebunny/crossref_metadata_2025_split huggingface dataset:
High-Dose Therapy and Autologous Peripheral-Blood Stem-Cell Transplantation As Salvage Treatment for HIV-Associated Lymphoma in Patients Receiving Highly Active Antiretroviral Therapy
Authors: Re Alessandro , Cattaneo Chiara , Michieli Mariagrazia , Casari Salvatore , Spina Michele , Rupolo Maurizio , Allione Bernardino , Nosari Annamaria , Schiantarelli Clara , Viganò Mariagrazia , Izzi Immacolata , Ferremi Piero , Lanfranchi Arnalda , Mazzuccato Maurizio , Carosi Gianpiero , Tirelli Umberto , Rossi Giuseppe 
Published: October 2003

Purpose: High-dose therapy (HDT) and peripheral-blood stem-cell transplantation (PBSCT) in HIV-associated lymphoma (HIV-Ly) has been recently reported in selected patients. We describe the results of a multi-institutional program of HDT and PBSCT as salvage therapy in HIV-Ly responsive to highly active antiretroviral therapy (HAART) in unselected patients. Patients and Methods: Patients with resistant or relapsed HIV-Ly after first-line chemotherapy (CT) underwent PBSC collection after a course of second-line CT or cyclophosphamide and granulocyte colony-stimulating factor. Patients with chemotherapy-sensitive disease received carmustine, etoposide, cytarabine, and melphalan (BEAM regimen) and PBSC reinfusion. Effective HAART was maintained during the entire program. Results: Sixteen consecutive patients entered the program. Adequate collection of PBSC was obtained in 80% of patients (median CD34+ cells 6.8 × 106/kg). Three patients had early progression. Ten patients (62%) received PBSCT with prompt engraftment in all patients (neutrophils and platelet engraftment after a median of 10 days [range, 8 to 10 days] and 13 days [range, 8 to 18 days], respectively). No patients died as a result of opportunistic or other infections or treatment-related complications. Eight of nine assessable patients achieved complete remission (one patient after radiotherapy for residual disease) and one patient achieved partial remission. Two patients experienced relapse and died at +10 and +14 months. Six patients are alive and disease free at a median of 8 months after transplantation. Conclusion: Our data confirm that HDT plus PBSCT is feasible and active as salvage therapy in HIV-Ly on a multi-institutional basis and in unselected HAART-responding patients. HIV infection should no longer preclude the opportunity of HDT in patients with lymphoma.
Breast Cancer in Older Women: Quality of Life and Psychosocial Adjustment in the 15 Months After Diagnosis
Authors: Ganz Patricia A. , Guadagnoli Edward , Landrum Mary Beth , Lash Timothy L. , Rakowski William , Silliman Rebecca A. 
Published: October 2003

Purpose: We examined the health-related quality of life (QOL) of a cohort of older women with breast cancer after their diagnosis. Patients and Methods: Six hundred ninety-one women aged 65 years and older were interviewed approximately 3 months after breast cancer surgery and two additional times in the following year using standardized QOL measures. Demographic factors, breast cancer treatments, and comorbid conditions were used to model ratings of health-related QOL over time. Self-perceived health and psychosocial adjustment at 15 months after surgery were modeled. Results: Physical and mental health scores declined significantly in the follow-up year, independent of age. However, a cancer-specific psychosocial instrument showed significant improvement in scores. Better 3-month physical and mental health scores, as well as better emotional social support, predicted more favorable self-perceived health 15 months after surgery. Psychosocial adjustment at 15 months was significantly predicted by better mental health, emotional social support, and better self-rated interaction with health care providers assessed at 3 months. Conclusion: Contrary to reports from younger women with breast cancer, we observed significant declines in the physical and mental health of older women in the 15 months after breast cancer surgery, whereas scores on a cancer-specific psychosocial QOL measure improved over time, consistent with patterns in younger women. Predictive models indicate that older women with impaired physical functioning, mental health, and emotional social support after surgery have poorer self-perceived health and psychosocial adjustment 1 year later. Interventions to address the physical and emotional needs of older women with breast cancer should be developed and evaluated to determine their impact on subsequent health-related QOL.
Clinical and Immunologic Results of a Randomized Phase II Trial of Vaccination Using Four Melanoma Peptides Either Administered in Granulocyte-Macrophage Colony-Stimulating Factor in Adjuvant or Pulsed on Dendritic Cells
Authors: Slingluff Craig L. , Petroni Gina R. , Yamshchikov Galina V. , Barnd Donna L. , Eastham Shannon , Galavotti Holly , Patterson James W. , Deacon Donna H. , Hibbitts Sarah , Teates David , Neese Patrice Y. , Grosh William W. , Chianese-Bullock Kimberly A. , Woodson Elizabeth M.H. , Wiernasz Catherine J. , Merrill Priscilla , Gibson Jennifer , Ross Maureen , Engelhard Victor H. 
Published: October 2003

Purpose: To determine clinical and immunologic responses to a multipeptide melanoma vaccine regimen, a randomized phase II trial was performed.Patients and Methods: Twenty-six patients with advanced melanoma were randomly assigned to vaccination with a mixture of four gp100 and tyrosinase peptides restricted by HLA-A1, HLA-A2, and HLA-A3, plus a tetanus helper peptide, either in an emulsion with granulocyte-macrophage colony-stimulating factor (GM-CSF) and Montanide ISA-51 adjuvant (Seppic Inc, Fairfield, NJ), or pulsed on monocyte-derived dendritic cells (DCs). Systemic low-dose interleukin-2 (Chiron, Emeryville, CA) was given to both groups. T-lymphocyte responses were assessed, by interferon gamma ELIspot assay (Chiron, Emeryville, CA), in peripheral-blood lymphocytes (PBLs) and in a lymph node draining a vaccine site (sentinel immunized node [SIN]).Results: In patients vaccinated with GM-CSF in adjuvant, T-cell responses to melanoma peptides were observed in 42% of PBLs and 80% of SINs, but in patients vaccinated with DCs, they were observed in only 11% and 13%, respectively. The overall immune response was greater in the GM-CSF arm (P < .02). Vitiligo developed in two of 13 patients in the GM-CSF arm but in no patients in the DC arm. Helper T-cell responses to the tetanus peptide were detected in PBLs after vaccination and correlated with T-cell reactivity to the melanoma peptides. Objective clinical responses were observed in two patients in the GM-CSF arm and one patient in the DC arm. Stable disease was observed in two patients in the GM-CSF arm and one patient in the DC arm.Conclusion: The high frequency of cytotoxic T-lymphocyte responses and the occurrence of clinical tumor regressions support continued investigation of multipeptide vaccines administered with GM-CSF in adjuvant.
Phase III Trial of Long-Term Adjuvant Androgen Deprivation After Neoadjuvant Hormonal Cytoreduction and Radiotherapy in Locally Advanced Carcinoma of the Prostate: The Radiation Therapy Oncology Group Protocol 92–02
Authors: Hanks Gerald E. , Pajak Thomas F. , Porter Arthur , Grignon David , Brereton Harmart , Venkatesan Varagur , Horwitz Eric M. , Lawton Colleen , Rosenthal Seth A. , Sandler Howard M. , Shipley William U. 
Published: October 2003

Purpose: Radiation Therapy Oncology Group (RTOG) Protocol 92–02 was a randomized trial testing long-term (LT) adjuvant androgen deprivation (AD) after initial AD with external-beam radiotherapy (RT) in patients with locally advanced prostate cancer (PC; T2c-4) and with prostate-specific antigen level less than 150 ng/mL. Patients and Methods: Patients received a total of 4 months of goserelin and flutamide, 2 months before and 2 months during RT. A radiation dose of 65 to 70 Gy was given to the prostate and a dose of 44 to 50 Gy to the pelvic lymph nodes. Patients were randomly assigned to receive no additional therapy (short-term [ST]AD-RT) or 24 months of goserelin (LTAD-RT); 1,554 patients were entered onto the study. Results: The LTAD-RT arm showed significant improvement in all efficacy end points except overall survival (OS; 80.0% v 78.5% at 5 years, P = .73), compared with the STAD-RT arm. In a subset of patients not part of the original study design, with tumors assigned Gleason scores of 8 to 10 by the contributing institutions, the LTAD-RT arm had significantly better OS (81.0% v 70.7%, P = .044). There was a small but significant increase in the frequency of late radiation grades 3, 4, and 5 gastrointestinal toxicity ascribed to the LTAD-RT arm (2.6% v 1.2% at 5 years, P = .037), the cause of which is not clear. Conclusion: The RTOG 92–02 trial supports the addition of LT adjuvant AD to STAD with RT for T2c-4 PC. In the exploratory subset analysis of patients with Gleason scores 8 to 10, LT adjuvant AD resulted in a survival advantage.
Attenuation by Reactive Oxygen Species of Glucocorticoid Suppression on Proopiomelanocortin Gene Expression in Pituitary Corticotroph Cells
Authors: Asaba Koichi , Iwasaki Yasumasa , Yoshida Masanori , Asai Masato , Oiso Yutaka , Murohara Toyoaki , Hashimoto Kozo 
Published: October 2003

AbstractUp-regulation of hypothalamo-pituitary-adrenal axis is maintained during acute inflammation and/or infection, in the face of sustained elevation of plasma glucocorticoid hormone. Inflammatory stress is usually associated with high plasma cytokine levels and increased generation of reactive oxygen species (ROS) as well. In this study, we examined the effect of ROS on the negative feedback regulation of glucocorticoid in hypothalamo-pituitary-adrenal axis using AtT20 corticotroph cells in vitro. When the cells were treated with H2O2, glucocorticoid suppression on the proopiomelanocortin gene promoter activity was attenuated in a dose-dependent manner. H2O2 also inhibited the ligand-stimulated nuclear translocation of glucocorticoid receptor. The released glucocorticoid suppression by H2O2 was not observed when the cells were cotreated with antioxidants. Together, these results suggest that increased ROS generation in the oxidative redox state attenuates the glucocorticoid negative feedback system, at least in part, by interfering with the nuclear translocation of glucocorticoid receptor and eliminating the repression on proopiomelanocortin gene expression.
Corticotropin-Releasing Hormone and Its Structurally Related Urocortin Are Synthesized and Secreted by Human Mast Cells
Authors: Kempuraj Duraisamy , Papadopoulou Nikoletta G. , Lytinas Michael , Huang Man , Kandere-Grzybowska Kristiana , Madhappan Bhuvaneshwari , Boucher William , Christodoulou Spyridon , Athanassiou Achilles , Theoharides Theoharis C. 
Published: October 2003

AbstractStress activates the hypothalamic-pituitary-adrenal axis through CRH, leading to production of glucocorticoids that down-regulate immune responses. However, acute stress also has proinflammatory effects. We previously showed that restraint stress, as well as CRH and its structurally related urocortin (Ucn), could activate mast cells and trigger mast cell-dependent vascular permeability. Here we show for the first time that human cord blood-derived cultured mast cells (hCBMC) at 10 wk, but not at 2 wk, are immunocytochemically positive for CRH and Ucn; human leukemic mast cells are weakly positive for both peptides. The ability of these mast cells to synthesize CRH and Ucn was confirmed by showing mRNA expression with RT-PCR. hCBMC (8–14 wk) synthesize and store 1–10 ng/106 cells (10–20 μg/g) of both CRH and Ucn detected by ELISA of cell homogenates. Stimulation of IgE-sensitized hCBMC with anti-IgE results in secretion of most CRH and Ucn. These findings indicate that mast cells are not only the target, but also a potential source of CRH and Ucn that could have both autocrine and paracrine functions, especially in allergic inflammatory disorders exacerbated by stress.
Cell-Specific Pituitary Gene Expression Profiles after Treatment with Leukemia Inhibitory Factor Reveal Novel Modulators for Proopiomelanocortin Expression
Authors: Abbud Rula A. , Kelleher Robert , Melmed Shlomo 
Published: October 2003

AbstractLeukemia inhibitory factor (LIF) mediates the hypothalamo-pituitary-adrenal stress response. Transgenic mice overexpressing LIF in the developing pituitary have altered pituitary differentiation with expansion of corticotropes, maintenance of Rathke’s cleft cysts, and suppression of all other pituitary cell types. Affymetrix GeneChips were used to identify modulators of LIF effects in corticotrope (AtT-20) and somatolactotrope (GH3) cells. In addition to genes known to respond to LIF in corticotrope cells [e.g. suppressor of cytokine signaling-3 (SOCS-3), signal transducer and activator of transcription-3, SH2 domain-containing tyrosine phosphatase-1, and proopiomelanocortin (POMC)], corticotrope-specific changes were also observed for genes involved in glycolysis and gluconeogenesis, transcription factors, signaling molecules, and expressed sequence tags. Two transcription factors identified, CCAAT/enhancer-binding protein β (C/EBPβ) and glial cell-derived neurotrophic factor (GDNF)-inducible factor (GIF), dose-dependently induced expression of the rat POMC promoter when overexpressed in AtT-20 cells. LIF further induced POMC transcription with C/EBPβ, but not with GIF. C/EBPβ also induced expression of the SOCS-3 promoter that was further enhanced by cotreatment with LIF. However, GIF did not affect SOCS-3 expression. These results indicate that C/EBPβ and GIF are downstream effectors of LIF corticotrope action. LIF also stimulates the expression of inhibitors of its actions, such as SOCS-3 and SH2 domain-containing tyrosine phosphatase-1. α2-HS-glycoprotein (AHSG)/fetuin, a secreted protein that antagonizes bone TGFβ/bone morphogenic protein signaling, was induced by LIF in a signal transducer and activator of transcription-3-dependent fashion. Pretreatment with AHSG/fetuin blocked LIF-induced expression of the POMC promoter independently of SOCS-3. Thus, using GeneChips, C/EBPβ and GIF have been identified as novel mediators and AHSG/fetuin as an inhibitor of LIF action in corticotropes.
Valproate Potentiates Androgen Biosynthesis in Human Ovarian Theca Cells
Authors: Nelson-DeGrave Velen L. , Wickenheisser Jessica K. , Cockrell Jennifer E. , Wood Jennifer R. , Legro Richard S. , Strauss Jerome F. , McAllister Jan M. 
Published: October 2003

Abstract
In patients with epilepsy, treatment with valproate (VPA) has been reported to be associated with polycystic ovary syndrome-like symptoms including weight gain, hyperandrogenemia, and hyperinsulinemia. We examined the effect of VPA on androgen biosynthesis in ovarian theca cells isolated from follicles of normal cycling women to determine whether the hyperandrogenemia reported with VPA treatment could be a result of direct effects of VPA on the ovary. In long-term cultures of theca cells treated for 72 h with sodium valproate (30–3000 μm), we observed an increase in basal and forskolin-stimulated dehydroepiandrosterone (DHEA), androstenedione, and 17α-hydroxyprogesterone production compared with control values. In contrast, low doses of VPA treatment (i.e. 30–300 μm) had no effect on basal and forskolin-stimulated progesterone production, whereas higher doses of VPA (1000–3000 μm) inhibited progesterone production. The most pronounced effect of VPA on androgen biosynthesis was observed in the dose range of 300-3000 μm, which represent therapeutic levels in the treatment of epilepsy and bipolar disorder. Western analyses demonstrated that VPA treatment increased both basal and forskolin-stimulated P450c17 and P450scc protein levels, whereas the amount of steroidogenic acute regulatory protein was unaffected. In transient transfection studies, VPA was found to increase P450 17α-hydroxylase and P450 cholesterol side-chain cleavage promoter activity, whereas steroidogenic acute regulatory protein promoter activity was unaffected. Consistent with the ability of VPA to act as a histone deacetylase (HDAC) inhibitor in other cell systems, VPA (500 μm) treatment was observed to increase histone H3 acetylation and P450 17α-hydroxylase mRNA accumulation. The HDAC inhibitor butyric acid (500 μm) similarly increased histone H3 acetylation and DHEA biosynthesis, whereas the VPA derivative valpromide (500 μm), which lacks HDAC inhibitory activity, had no effect on histone acetylation or DHEA biosynthesis. These data suggest that VPA-induced ovarian androgen biosynthesis results from changes in chromatin modifications (histone acetylation) that augment transcription of steroidogenic genes. These studies provide the first biochemical evidence to support a role for VPA in the genesis of polycystic ovary syndrome-like symptoms, and establish a direct link between VPA treatment and increased ovarian androgen biosynthesis.
Desensitization and Endocytosis Mechanisms of Ghrelin-Activated Growth Hormone Secretagogue Receptor 1a
Authors: Camiña Jesus P. , Carreira Marcos C. , El Messari Said , Llorens-Cortes Catherine , Smith Roy G. , Casanueva Felipe F. 
Published: October 2003

AbstractIn this study, a sequential analysis of pathways involved in the regulation of GH secretagogue receptor subtype 1a (GHSR-1a) signaling has been undertaken to characterize the process of rapid desensitization that is observed after ghrelin binding. This process was evaluated by studying the binding of [125I]ghrelin, measurement of intracellular calcium mobilization, and confocal microscopy. The results indicate that GHSR-1a is mainly localized at the plasma membrane under unstimulated conditions and rapidly desensitizes after stimulation. The agonist-dependent desensitization is not mediated by protein kinase C because phorbol ester, phorbol-12-myristate-13-acetate, failed to block the ghrelin-induced calcium response. The ghrelin/GHSR-1a complex progressively disappears from the plasma membrane after 20 min exposure to ghrelin and accumulates in the perinuclear region after 60 min. Colocalization of the internalized GHSR-1a with the early endosome marker (EEA1) after 20 min exposure to ghrelin suggests that endocytosis occurs via clathrin-coated pits, which is consistent with the lack of internalization of this receptor observed after potassium depletion. Different from other G protein-coupled receptors, GHSR-1a showed slow recycling. Surface binding slowly recovered after agonist treatment and returned to control levels within 360 min. Furthermore, inhibition of vacuolar H+-ATPases prevented recycling of the receptor, suggesting that the nondissociation of the ligand/receptor complex is responsible for this effect. The GHSR-1a internalization may explain the characteristic physiological responses mediated by this receptor.
Nuclear Factor-κB Activates Transcription of the Androgen Receptor Gene in Sertoli Cells Isolated from Testes of Adult Rats
Authors: Zhang Liying , Charron Martin , Wright William W. , Chatterjee Bandana , Song Chung S. , Roy Arun K. , Brown Terry R. 
Published: October 2003

Abstract
The androgen receptor (AR) in Sertoli cells mediates the actions of testosterone on spermatogenesis. However, the transcription factors responsible for AR gene regulation in Sertoli cells remain unknown. In this study, we determined that nuclear factor-κB (NF-κB) regulates transcription of AR in primary cultures of Sertoli cells isolated from testes of adult rats. Electrophoretic mobility shift and antibody supershift assays with nuclear extracts prepared from Sertoli cells identified two binding sites, termed κB1 at −491/−482 bp and κB2 at −574/−565 bp, upstream of the transcription start site of the AR gene that bind the NF-κB subunits, p50 and p65. DNAse I footprint analyses showed that binding of the p50 NF-κB subunit protected the same regions on the rat AR promoter. Analyses of AR promoter-luciferase reporter gene activity after transfection of primary cultures of Sertoli cells demonstrated that mutation of the κB2 site or combined mutation of the κB1 and κB2 sites reduced activity by 40%. Preferential binding of the transcriptionally active p65/p50 heterodimer to the κB2 site rather than to the κB1 site supported these observations. Overexpression of the NF-κB p65 and p50 subunits in Sertoli cells increased activity from the wild-type AR promoter and the promoter with mutation of the κB1 site, but not the κB2 site. Activity was further stimulated by CBP (CREB binding protein), a coactivator of p65 transcriptional activity. Taken together, our data show that NF-κB is an activator of AR gene transcription in Sertoli cells and may be an important determinant of androgen activity during spermatogenesis.
Low-Dose Immunization with Adenovirus Expressing the Thyroid-Stimulating Hormone Receptor A-Subunit Deviates the Antibody Response toward That of Autoantibodies in Human Graves’ Disease
Authors: Chen Chun-Rong , Pichurin Pavel , Chazenbalk Gregorio D. , Aliesky Holly , Nagayama Yuji , McLachlan Sandra M. , Rapoport Basil 
Published: October 2003

AbstractImmunization with adenovirus expressing the TSH receptor (TSHR) induces hyperthyroidism in 25–50% of mice. Even more effective is immunization with a TSHR A-subunit adenovirus (65–84% hyperthyroidism). Nevertheless, TSHR antibody characteristics in these mice do not mimic accurately those of autoantibodies in typical Graves’ patients, with a marked TSH-blocking antibody response. We hypothesized that this suboptimal antibody response was consequent to the standard dose of TSHR-adenovirus providing too great an immune stimulus. To test this hypothesis, we compared BALB/c mice immunized with the usual number (1011) and with far fewer viral particles (109 and 107). Regardless of viral dose, hyperthyroidism developed in a similar proportion (68–80%) of mice. We then examined the qualitative nature of TSHR antibodies in each group. Sera from all mice had TSH binding-inhibitory (TBI) activity after the second immunization, with TBI values in proportion to the viral dose. After the third injection, all groups had near-maximal TBI values. Remarkably, in confirmation of our hypothesis, immunization with progressively lower viral doses generated TSHR antibodies approaching the characteristics of autoantibodies in human Graves’ disease as follows: 1) lower TSHR antibody titers on ELISA and 2) lower TSH-blocking antibody activity without decrease in thyroid-stimulating antibody activity. In summary, low-dose immunization with adenovirus expressing the free TSHR A-subunit provides an induced animal model with a high prevalence of hyperthyroidism as well as TSHR antibodies more closely resembling autoantibodies in Graves’ disease.
TheChironomus tentanstranslation initiation factor eIF4H is present in the nucleus but does not bind to mRNA until the mRNA reaches the cytoplasmic perinuclear region
Authors: Björk Petra , Baurén Göran , Gelius Birgitta , Wrange Örjan , Wieslander Lars 
Published: October 2003

In the cell nucleus, precursors to mRNA, pre-mRNAs, associate with a large number of proteins and are processed to mRNA-protein complexes, mRNPs. The mRNPs are then exported to the cytoplasm and the mRNAs are translated into proteins. The mRNAs containing in-frame premature stop codons are recognized and degraded in the nonsense-mediated mRNA decay process. This mRNA surveillence may also occur in the nucleus and presumably involves components of the translation machinery. Several translation factors have been detected in the nucleus, but their functional relationship to the dynamic protein composition of pre-mRNPs and mRNPs in the nucleus is still unclear.Here, we have identified and characterized the translation initiation factor eIF4H in the dipteran Chironomus tentans. In the cytoplasm, Ct-eIF4H is associated with poly(A+) RNA in polysomes. We show that a minor fraction of Ct-eIF4H enters the nucleus. This fraction is independent on the level of transcription. CteIF4H could not be detected in gene-specific pre-mRNPs or mRNPs, nor in bulk mRNPs in the nucleus. Our immunoelectron microscopy data suggest that Ct-eIF4H associates with mRNP in the cytoplasmic perinuclear region, immediately as the mRNP exits from the nuclear pore complex.