bluuebunny/crossref_metadata_2025_split huggingface dataset:
Prophylaxis of Radiation-Associated Mucositis in Conventionally Treated Patients With Head and Neck Cancer: A Double-Blind, Phase III, Randomized, Controlled Trial Evaluating the Clinical Efficacy of an Antimicrobial Lozenge Using a Validated Mucositis Scoring System
Authors: El-Sayed S. , Nabid A. , Shelley W. , Hay J. , Balogh J. , Gelinas M. , MacKenzie R. , Read N. , Berthelet E. , Lau H. , Epstein J. , Delvecchio P. , Ganguly P. K. , Wong F. , Burns P. , Tu D. , Pater J. 
Published: September 2002

PURPOSE: Mucositis occurs in almost all patients treated with radiotherapy for head and neck cancer. The aim of this multicenter, double-blind, prospective, randomized trial was to evaluate the clinical efficacy of an economically viable antimicrobial lozenge (bacitracin, clotrimazole, and gentamicin [BcoG]) in the alleviation of radiation-induced mucositis in patients with head and neck cancer. PATIENTS AND METHODS: One hundred thirty-seven eligible patients were randomized to treatment with either antimicrobial lozenge (69 patients) or placebo lozenge (68 patients). The primary end point of the study was the time to development of severe mucositis from the start of radiotherapy. Secondary end points included severity and duration of mucositis, pain measurement, radiation therapy interruption, and quality of life. Mucositis was scored using a validated mucositis scoring system. RESULTS: Toxicity profiles were similar between the two arms of the study. The median time to development of severe mucositis from the start of radiotherapy was 3.61 weeks on BCoG and 3.96 weeks on placebo (P = .61). There were no statistically significant differences between the arms in the extent of severe mucositis as measured by physician, in oral toxicities as recorded by patients, or in radiotherapy delays. CONCLUSION: This study was conducted on the basis of a pilot study that demonstrated the BCoG lozenge to be tolerable and microbiologically efficacious. A validated mucositis scoring system was used. However, in this group of patients treated with conventional radiotherapy, the lozenge did not impact significantly on the severity of mucositis. Whether such a lozenge would be beneficial in treatment situations where rate of severe mucositis is higher (ie, in patients treated with unconventional fractionation or with concomitant chemotherapy) is unknown.
Tyrosinase mRNA in Blood of Patients With Melanoma Treated With Adjuvant Interferon
Authors: Mellado Begoña , del Carmen Vela Maria , Colomer Dolors , Gutierrez Lorena , Castel Teresa , Quintó Llorenç , Fontanillas Montserrat , Reguart Noemi , Domingo-Domènech José M. , Montagut Clara , Estapé Jordi , Gascón Pedro ,   Melanoma Group
Published: September 2002

PURPOSE: To evaluate the clinical significance of the detection of circulating melanoma cells in patients treated with adjuvant interferon and to determine their potential value as a marker of interferon response. PATIENTS AND METHODS: We prospectively analyzed 616 peripheral-blood samples from 120 melanoma patients with stage IIA (n = 33), IIB (n = 22), III (n = 50), or IV (surgically resected) (n = 15) disease receiving adjuvant interferon alfa-2b therapy. Tyrosinase mRNA was assayed by reverse transcriptase polymerase chain reaction (RT-PCR) as a marker of circulating melanoma cells before the start of interferon and every 2 to 3 months thereafter. RESULTS: With a median follow-up time of 32.3 months (range, 7.1 to 77.5 months), 47 patients (39.8%) relapsed and 31 (26%) died. During adjuvant interferon treatment, 76 patients (64%) had undetected circulating melanoma cells and 44 patients (36%) had a positive RT-PCR result in at least one sample. Actuarial 5-year disease-free survival was 62% in patients with persistently negative RT-PCR during interferon treatment and 38% for patients with positive RT-PCR during interferon (P = .02). Actuarial 5-year overall survival was 75% and 50%, respectively (P = .03). CONCLUSION: Patients with melanoma and tyrosinase mRNA detected in the blood during adjuvant interferon therapy had a worse prognosis compared with patients with undetected tyrosinase mRNA during treatment. Further investigation into the detection of circulating melanoma cells as a surrogate marker of response to adjuvant interferon therapy is warranted.
Nomogram for Overall Survival of Patients With Progressive Metastatic Prostate Cancer After Castration
Authors: Smaletz Oren , Scher Howard I. , Small Eric J. , Verbel David A. , McMillan Alex , Regan Kevin , Kelly W. Kevin , Kattan Michael W. 
Published: September 2002

PURPOSE: To develop a pretreatment prognostic model for survival of patients with progressive metastatic prostate cancer after castration using parameters that are measured during routine clinical management. PATIENTS AND METHODS: Pretreatment clinical and biochemical determinants from 409 patients enrolled onto 19 consecutive therapeutic protocols from June 1989 through January 2000 were evaluated. The factors selected were age, Karnofsky performance status (KPS), hemoglobin (HGB), prostate-specific antigen (PSA), lactate dehydrogenase (LDH), alkaline phosphatase (ALK), and albumin. These factors were combined in an accelerated failure time regression model to produce a nomogram to predict median, 1-year, and 2-year survival. The nomogram was validated internally and externally using data from a multicenter randomized trial of suramin plus hydrocortisone versus hydrocortisone alone. RESULTS: The median survival of the entire group was 15.8 months (range, 0.9 to 77.8 months); 87% have died. In multivariable analysis, KPS, HGB, ALK, albumin, and LDH were significantly associated with survival (P < .05), whereas age and PSA were not. All seven factors were included in the nomogram. When applied to the external validation data set, the nomogram achieved a concordance index of 0.67. Calibration plots suggested that the nomogram was well calibrated for all predictions. CONCLUSION: A nomogram derived from pretreatment parameters that are measured on a routine basis was constructed. It can be used to predict the median, 1-year, and 2-year survival of patients with progressive castrate metastatic disease with reasonable accuracy. The information is useful to assess prognosis, guide treatment selection, and design clinical trials.
Role of Nonmyeloablative Allogeneic Stem-Cell Transplantation After Failure of Autologous Transplantation in Patients With Lymphoproliferative Malignancies
Authors: Branson Katharine , Chopra Rajesh , Kottaridis Panagiotis D. , McQuaker Grant , Parker Anne , Schey Stephen , Chakraverty Ronjon K. , Craddock Charles , Milligan Donald W. , Pettengell Ruth , Marsh Judith C.W. , Linch David C. , Goldstone Anthony H. , Williams Catherine D. , Mackinnon Stephen 
Published: September 2002

PURPOSE: Conventional allogeneic stem-cell transplantation (SCT) after a prior failed autograft is associated with a transplant-related mortality rate of 50% to 80%. The aim of the current study was to evaluate the safety and efficacy of sibling, HLA-matched, nonmyeloablative allogeneic SCT with donor lymphocyte infusion (DLI) in patients with lymphoid malignancy after failure of autologous SCT. PATIENTS AND METHODS: A total of 38 patients with refractory, progressive, or relapsed disease after autologous SCT were entered onto this study. The conditioning regimen consisted of the humanized monoclonal antibody CAMPATH-1H, fludarabine, and melphalan. Fifteen of 35 assessable patients received DLI after SCT. RESULTS: Sustained neutrophil engraftment was achieved in 37 recipients, and platelet engraftment was achieved in 35 patients. The estimated transplant-related mortality was 7.9% at day 100 and 20% at 14 months, the median duration of follow-up. Eight patients experienced grade I/II acute graft-versus-host disease (GVHD) after transplantation, but no grade III/IV GVHD was observed in this setting. However, grade III/IV GVHD occurred in seven patients who received DLI. The actuarial overall survival at 14 months was 53%, with a progression-free survival of 50%. DLI produced a further response in three of 15 recipients. CONCLUSION: Nonmyeloablative allogeneic SCT after CAMPATH-1H–containing conditioning is a relatively safe option compared with conventional allogeneic transplantation for patients who have failed previous autologous SCT. The low incidence of early GVHD enabled the subsequent administration of DLI to improve further clinical responses in this poor-risk group of lymphoma and myeloma patients.
Biweekly Chemotherapy With Oxaliplatin, Irinotecan, Infusional Fluorouracil, and Leucovorin: A Pilot Study in Patients With Metastatic Colorectal Cancer
Authors: Falcone Alfredo , Masi Gianluca , Allegrini Giacomo , Danesi Romano , Pfanner Elisabetta , Brunetti Isa Maura , Di Paolo Antonello , Cupini Samanta , Del Tacca Mario , Conte Pierfranco 
Published: September 2002

PURPOSE: To determine the feasibility, recommended doses, plasma pharmacokinetics, and antitumor activity of a biweekly chemotherapy regimen with oxaliplatin (L-OHP), irinotecan (CPT-11), infusional fluorouracil (5-FU), and leucovorin (LV) in metastatic colorectal cancer patients. PATIENTS AND METHODS: Patients received CPT-11 followed by L-OHP and LV 200 mg/m2 and followed by 5-FU 3,800 mg/m2 as a 48-hour infusion, repeated every 2 weeks. In the first part of the study, an escalation of CPT-11 dose and/or a decrease of the L-OHP dose were planned. Once the recommended doses of CPT-11 and L-OHP were determined, all subsequent patients were treated at the recommended doses. RESULTS: Forty-two patients entered the study. CPT-11 175 mg/m2 and L-OHP 100 mg/m2 in combination with LV 200 mg/m2 and 5-FU 3,800 mg/m2 could be administered with acceptable toxicities; 39 patients were treated at these dose levels. The pharmacokinetics parameters of the agents used and their metabolites did not seem to be influenced by the concomitant use of the other drugs. The most relevant toxicities were diarrhea and neutropenia, with 14% of patients experiencing one episode of febrile neutropenia. In five patients (11.9%) a complete and in 25 (59.5%) a partial response was demonstrated, for an objective response rate of 71.4% (95% confidence interval, 47% to 83%). In 11 patients (26%), a surgical resection of residual disease could be performed. Median progression-free and overall survival times were 10.4 and 26.5 months, respectively. CONCLUSION: This biweekly regimen is feasible and has acceptable and manageable toxicities and no apparent relevant pharmacokinetics interactions. This combination is associated with a promising antitumor activity, time to progression, and survival. A phase III randomized trial in Italy planned by the Gruppo Oncologico Nord Ovest has just started.
Characterization of a Novel and Functional Human Prolactin Receptor Isoform (ΔS1PRLr) Containing Only One Extracellular Fibronectin-Like Domain
Authors: Kline J. Bradford , Rycyzyn Michael A. , Clevenger Charles V. 
Published: September 2002

AbstractProlactin (PRL)-dependent signaling occurs as the result of ligand-induced homodimerization of the PRL receptor (PRLr). To date, short, intermediate, and long human PRLr isoforms have been characterized. To investigate the expression of other possible human PRLr isoforms, RT-PCR was performed on mRNA isolated from the breast carcinoma cell line T47D. A 1.5-kb PCR fragment was isolated, subcloned, and sequenced. The PCR product exhibited a nucleotide sequence 100% homologous to the human long isoform except bp 71–373 were deleted, which code for the S1 motif of the extracellular domain. Therefore, this isoform was designated the ΔS1 PRLr. Northern analysis revealed variable ΔS1 PRLr mRNA expression in a variety of tissues. Transfection of Chinese hamster ovary cells with ΔS1 cDNA showed the isoform is expressed at the protein level on the cell surface with a molecular mass of approximately 70 kDa. Kinetic studies indicated the ΔS1 isoform bound ligand at a lower affinity than wild-type receptor. The ΔS1 PRLr was also shown to activate the proximal signaling molecule Jak2 upon addition of ligand to transfected cells, and, unlike the long PRLr, high concentrations of ligand did not function as a self-antagonist to signaling during intervals of PRL serum elevation, i.e. stress and pregnancy. Given its apparent widespread expression, this PRLr isoform may contribute to PRL action. Furthermore, the functionality of this receptor raises interesting questions regarding the minimal extracellular domain necessary for ligand-induced receptor signaling.
Identification of Indian Hedgehog as a Progesterone-Responsive Gene in the Murine Uterus
Authors: Takamoto Norio , Zhao Bihong , Tsai Sophia Y. , DeMayo Francesco J. 
Published: September 2002

AbstractProgesterone (P4) plays a central role in normal uterine function, from embryo implantation in endometrium to establishment and maintenance of uterine quiescence during pregnancy in the myometrium. Considering its diverse physiological effects on female reproductive function, rather little is known about downstream events of P4 action. Recent progress in differential screening technologies facilitated identification of such inducible genes. We used uteri of wild-type and progesterone receptor null mutant mice as a starting material and screened for differentially expressed genes by medium-density cDNA expression array. Here, we report that the expression of the morphogen, Indian hedgehog (Ihh), is rapidly stimulated by P4 in the mouse uterus. The level of Ihh mRNA is induced within 3 h, after a single administration of P4 to ovariectomized mice. The induced Ihh mRNA and protein were localized to the luminal and glandular epithelial compartment of the endometrium. During pseudopregnancy, the Ihh mRNA level was transiently increased in the preimplantation period and d 3 and d 4 post coitum and then decreased rapidly at d 5 post coitum. Furthermore, the expression profile of patched-1, hedgehog interacting protein-1, and chicken ovalbumin upstream promoter-transcription factor II, genes known to be in the hedgehog signaling pathway in other tissues, followed the expression pattern of Ihh during the periimplantation period. Our results suggested that Ihh is regulated by P4, and the Ihh signaling axis may play a role in the preparation of the uterus for implantation during the periimplantation period.
Dopamine-D2S Receptor Inhibition of Calcium Influx, Adenylyl Cyclase, and Mitogen-Activated Protein Kinase in Pituitary Cells: Distinct Gα and Gβγ Requirements
Authors: Banihashemi Behzad , Albert Paul R. 
Published: September 2002

AbstractThe G protein specificity of multiple signaling pathways of the dopamine-D2S (short form) receptor was investigated in GH4ZR7 lactotroph cells. Activation of the dopamine-D2S receptor inhibited forskolin-induced cAMP production, reduced BayK8644- activated calcium influx, and blocked TRH-mediated p42/p44 MAPK phosphorylation. These actions were blocked by pretreatment with pertussis toxin (PTX), indicating mediation by Gi/o proteins. D2S stimulation also decreased TRH-induced MAPK/ERK kinase phosphorylation. TRH induced c-Raf but not B-Raf activation, and the D2S receptor inhibited both TRH-induced c-Raf and basal B-Raf kinase activity. After PTX treatment, D2S receptor signaling was rescued in cells stably transfected with individual PTX-insensitive Gα mutants. Inhibition of adenylyl cyclase was partly rescued by Gαi2 or Gαi3, but Gαo alone completely reconstituted D2S-mediated inhibition of BayK8644-induced L-type calcium channel activation. Gαo and Gαi3 were the main components involved in D2S-mediated p42/44 MAPK inhibition. In cells transfected with the carboxyl-terminal domain of G protein receptor kinase to inhibit Gβγ signaling, only D2S-mediated inhibition of calcium influx was blocked, but not inhibition of adenylyl cyclase or MAPK. These results indicate that the dopamine-D2S receptor couples to distinct Gi/o proteins, depending on the pathway addressed, and suggest a novel Gαi3/Gαo-dependent inhibition of MAPK mediated by c-Raf and B-Raf-dependent inhibition of MAPK/ERK kinase.
Identification of an Androgen-Dependent Enhancer within the Prostate Stem Cell Antigen Gene
Authors: Jain Anjali , Lam Amanda , Vivanco Igor , Carey Michael F. , Reiter Robert E. 
Published: September 2002

AbstractProstate stem cell antigen (PSCA) is emerging as an important diagnostic marker and therapeutic target in prostate cancer. Previous studies indicated that PSCA was directly regulated by androgens, but the mechanism has not been elucidated. Here we describe the identification of a compact cell-specific and androgen-responsive enhancer between 2.7 and 3 kb upstream of the transcription start site. The enhancer functions autonomously when positioned immediately adjacent to a minimal promoter. Deoxyribonuclease I footprinting analysis with recombinant androgen receptor (AR) reveals that the enhancer contains two AR binding sites at one end. Mutational analysis of the AR binding sites revealed the importance of the higher affinity one. The dissociation constant of the high affinity binding site (androgen response element I) was determined to be approximately 87 nm. The remainder of the enhancer contains elements that function synergistically with the AR. We discuss the structural organization of the PSCA enhancer and compare it with that found in other AR-regulated genes.
The Roles of Androgen Receptors and Androgen-Binding Proteins in Nongenomic Androgen Actions
Authors: Heinlein Cynthia A. , Chang Chawnshang 
Published: September 2002

AbstractThe biological activity of testosterone and dihydrotestosterone is thought to occur predominantly through binding to the androgen receptor (AR), a member of the nuclear receptor superfamily that functions as a ligand-activated transcription factor. However, androgens have also been reported to induce the rapid activation of kinase-signaling cascades and modulate intracellular calcium levels. These effects are considered to be nongenomic because they occur in cell types that lack a functional AR, in the presence of inhibitors of transcription and translation, or are observed to occur too rapidly to involve changes in gene transcription. Such nongenomic effects of androgens may occur through AR functioning in the cytoplasm to induce the MAPK signal cascade. In addition, androgens may function through the sex hormone binding globulin receptor and possibly a distinct G protein-coupled receptor to activate second messenger signaling mechanisms. The physiological effect of nongenomic androgen action has yet to be determined. However, it may ultimately contribute to regulation of transcription factor activity, including mediation of the transcriptional activity of AR.
Colocalization and Ligand-Dependent Discrete Distribution of the Estrogen Receptor (ER)α and ERβ
Authors: Matsuda Ken-ichi , Ochiai Ikuo , Nishi Mayumi , Kawata Mitsuhiro 
Published: September 2002

AbstractTo investigate the relationships between the loci expressing functions of estrogen receptor (ER)α and that of ERβ, we analyzed the subnuclear distribution of ERα and ERβ in response to ligand in single living cells using fusion proteins labeled with different spectral variants of green fluorescent protein. Upon activation with ligand treatment, fluorescent protein-tagged (FP)-ERβ redistributed from a diffuse to discrete pattern within the nucleus, showing a similar time course as FP-ERα, and colocalized with FP-ERα in the same discrete cluster. Analysis using deletion mutants of ERα suggested that the ligand-dependent redistribution of ERα might occur through a large part of the receptor including at least the latter part of activation function (AF)-1, the DNA binding domain, nuclear matrix binding domain, and AF-2/ligand binding domain. In addition, a single AF-1 region within ERα homodimer, or a single DNA binding domain as well as AF-1 region within the ERα/ERβ heterodimer, could be sufficient for the cluster formation. More than half of the discrete clusters of FP-ERα and FP-ERβ were colocalized with hyperacetylated histone H4 and a component of the chromatin remodeling complex, Brg-1, indicating that ERs clusters might be involved in structural changes of chromatin.
Cloning and Characterization of a Novel Endothelial Promoter of the Human CYP19 (Aromatase P450) Gene that Is Up-Regulated in Breast Cancer Tissue
Authors: Sebastian Siby , Takayama Kazuto , Shozu Makio , Bulun Serdar E. 
Published: September 2002

AbstractIntratumoral expression of aromatase P450 (P450arom) promotes the growth of breast tumors via increased local estrogen concentration. We cloned a novel 101-bp untranslated first exon (I.7) that comprises the 5′-end of 29–54% of P450arom transcripts isolated from breast cancer tissues (n = 7). The levels of P450arom transcripts with exon I.7 were significantly increased in breast tumor tissues and adipose tissue adjacent to tumors. We identified a promoter immediately upstream of exon I.7 and mapped this to about 36 kb upstream of ATG translation start site of the CYP19 (aromatase cytochrome P450) gene. Sequence analysis of I.7 revealed a TATA-less promoter containing an initiator, two consensus GATA sites, and cis-regulatory elements found in megakaryocytes and endothelial type promoters. Luciferase activity directed by the promoter I.7 sequence (−299/+81 bp) was 4-fold greater than a minimum length promoter sequence (−35/+81 bp) in human microvascular endothelial cells (HMEC-1), but only 2-fold greater in MCF-7 breast malignant epithelial cells. There was no promoter activity in primary breast adipose fibroblasts. Site-directed mutations demonstrated that maximal basal promoter activity required two GATA motifs at −146/−141 bp and −196/−191 bp. Gel shift and deoxyribonuclease I footprinting assays demonstrated the binding of GATA-2 transcription factor but not GATA-1 to the −196/−191-bp region. Overexpression of GATA-2 in HMEC-1 cells increases promoter I.7 activity by 5-fold. In conclusion, promoter I.7 is a GATA-2-regulated endothelial promoter of the human CYP19 gene and may increase estrogen biosynthesis in vascular endothelial cells of breast cancer. The activity of this promoter may also be important for intracrine and paracrine effects of estrogen on blood vessels.
Nuclear Export of Glucocorticoid Receptor is Enhanced by c-Jun N-Terminal Kinase-Mediated Phosphorylation
Authors: Itoh M. , Adachi M. , Yasui H. , Takekawa M. , Tanaka H. , Imai K. 
Published: September 2002

AbstractThe c-Jun N-terminal kinase (JNK) phosphorylates the glucocorticoid receptor (GR) and inhibits GR-mediated transcription. However, the biological effect of the GR phosphorylation remains unknown. Here we demonstrate that activated JNK phosphorylates human GR at Ser226 and enhances its nuclear export after withdrawal of a ligand for GR, dexamethasone. At 1 h after dexamethasone withdrawal, green fluorescent protein-GR molecules were mostly retained at the nucleus, whereas UV exposure enhanced its nuclear export, and approximately 30–40% of cells revealed distinct nuclear export. JNK overexpression alone mimics UV exposure and enhanced GR export accompanied by inhibition of GR-mediated transcription. However, mutation of the Ser226 JNK phosphorylation site in GR abrogated UV-mediated enhancement of GR nuclear export. Furthermore, overexpression of a dominant negative SEK1 mutant also abrogated the effects of UV exposure on GR export. Taken together, these findings suggest that JNK-mediated phosphorylation of the GR-Ser226 enhances GR nuclear export and may contribute to termination of GR-mediated transcription.