bluuebunny/crossref_metadata_2025_split huggingface dataset:
Correlation Between O6-Methylguanine-DNA Methyltransferase and Survival in Inoperable Newly Diagnosed Glioblastoma Patients Treated With Neoadjuvant Temozolomide
Authors: Chinot Olivier L. , Barrié Maryline , Fuentes Stephane , Eudes Nathalie , Lancelot Sophie , Metellus Philippe , Muracciole Xavier , Braguer Diane , Ouafik L'Houcine , Martin Pierre-Marie , Dufour Henry , Figarella-Branger Dominique 
Published: April 2007

Purpose This phase II study evaluated the efficacy and safety of a 7-day on/7-day off regimen of temozolomide before radiotherapy (RT) in patients with inoperable newly diagnosed glioblastoma. Patients and Methods Patients received temozolomide (150 mg/m2/d on days 1 to 7 and days 15 to 21 every 28 days; 7 days on/7 days off) for up to four cycles before conventional RT (2-Gy fractions to a total of 60 Gy) and for four cycles thereafter or until disease progression. The primary end point was tumor response. Tumor tissue from 25 patients was analyzed for O6-methylguanine-DNA methyltransferase (MGMT) expression. Results Twenty-nine patients with a median age of 60 years were treated, and 28 were assessable for response. Seven (24%) of 29 patients had a partial response, nine patients (31%) had stable disease, and 12 patients (41%) had progressive disease. Median progression-free survival (PFS) time was 3.8 months, and median overall survival (OS) time was 6.1 months. Patients with low MGMT expression, compared with patients with high MGMT expression, had a significantly higher response rate (55% v 7%, respectively; P = .004) and improved PFS (median, 5.5 v 1.9 months, respectively; P = .009) and OS (median, 16 v 5 months, respectively; P = .003). The most common grade 3 and 4 toxicities were thrombocytopenia (20%) and neutropenia (17%). Conclusion This dose-dense temozolomide regimen resulted in modest antitumor activity with an acceptable safety profile in the neoadjuvant setting, and expression of MGMT correlated with response to temozolomide. However, this treatment approach seems to be inferior to standard concomitant RT plus temozolomide.
Pretreatment Levels of Peripheral Neutrophils and Leukocytes As Independent Predictors of Overall Survival in Patients With American Joint Committee on Cancer Stage IV Melanoma: Results of the EORTC 18951 Biochemotherapy Trial
Authors: Schmidt Henrik , Suciu Stefan , Punt Cornelis J.A. , Gore Martin , Kruit Wim , Patel Poulam , Lienard Danielle , von der Maase Hans , Eggermont Alexander M.M. , Keilholz Ulrich 
Published: April 2007

Purpose An elevated count of blood neutrophils and monocytes recently was shown independently to predict short survival in patients with stage IV melanoma undergoing interleukin-2–based immunotherapy. In this study, we aimed to validate this finding in a large cohort of stage IV melanoma patients. Patients and Methods For this retrospective prognostic study, the data from the European Organisation for the Research and Treatment of Cancer 18951 study were used. Patients were randomly assigned between treatment with dacarbazine, cisplatin, and interferon alfa with or without interleukin-2. Counts of neutrophils and leukocytes were analyzed together with other known prognostic factors: serum lactate dehydrogenase, performance status, metastatic site, and sex. Two multivariate prognostic factor analyses were carried out in the model: one with leukocyte counts and one with neutrophil counts. Results A total of 363 patients were randomly assigned and baseline blood neutrophil and leukocyte counts were available from 316 and 350 patients, respectively. A high neutrophil count (> 7.5 × 109/L) was an independent prognostic factor for short overall survival (hazard ratio [HR], 1.5; 95% CI, 1.1 to 2.1; P = 0.02), and a high leukocyte count (> 10 × 109/L) was an independent prognostic factor of both short overall survival (HR, 1.7; 95% CI, 1.3 to 2.4; P = 0.0005) and short progression-free survival (HR, 1.5; 95% CI, 1.1 to 2.1; P = 0.008). Conclusion A high pretreatment count of neutrophils in blood was confirmed as an independent prognostic factor for short overall survival in stage IV melanoma patients undergoing interleukin-2–based immunotherapy. Furthermore, a high count of leukocytes was an independent prognostic factor for short overall survival and progression-free survival. Both parameters should be useful as stratification factors in clinical trials.
Phase I Trial and Pharmacokinetic Study of Pemetrexed in Children With Refractory Solid Tumors: The Children's Oncology Group
Authors: Malempati Suman , Nicholson H. Stacy , Reid Joel M. , Blaney Susan M. , Ingle Ashish M. , Krailo Mark , Stork Linda C. , Melemed Allen S. , McGovern Renee , Safgren Stephanie , Ames Matthew M. , Adamson Peter C. 
Published: April 2007

PurposeWe report results of a phase I trial and pharmacokinetic study of pemetrexed (LY231514) in children and adolescents with refractory solid tumors. Pemetrexed is a novel antifolate that inhibits multiple enzymes necessary for the biosynthesis of thymidine and purine nucleotides. The purpose of this study was to determine the maximum-tolerated dose (MTD), dose-limiting toxicities (DLTs), and pharmacokinetic properties of pemetrexed in children.Patients and MethodsPemetrexed was administered as a 10-minute intravenous infusion every 21 days. Patients received vitamin B12and folic acid supplementation as well as dexamethasone prophylaxis. Cohorts of three to six children were enrolled at dose levels of 400, 520, 670, 870, 1,130, 1,470, 1,910, and 2,480 mg/m2. Pharmacokinetic studies were performed during the first course of treatment.ResultsThirty-three patients (31 assessable) with a median age of 12 years were enrolled. DLT occurred in one of six patients at 1,470 mg/m2and two of four patients at 2,480 mg/m2. The MTD was 1,910 mg/m2. The primary DLTs were neutropenia and rash. No objective antitumor responses were seen. Mean plasma clearance, half-life, and steady-state volume of distribution values were 2.3 L/h/m2, 2.5 hours, and 5.4 L/m2, respectively.ConclusionPemetrexed is well-tolerated in children with refractory solid tumors at doses similar to the MTD in adults. The recommended dose for phase II studies is 1,910 mg/m2administered every 21 days with dexamethasone, folic acid, and vitamin B12supplementation.
Adjuvant Vinorelbine and Cisplatin in Elderly Patients: National Cancer Institute of Canada and Intergroup Study JBR.10
Authors: Pepe Carmela , Hasan Baktiar , Winton Timothy L. , Seymour Lesley , Graham Barbara , Livingston Robert B. , Johnson David H. , Rigas James R. , Ding Keyue , Shepherd Frances A. 
Published: April 2007

Purpose Recent trials have shown significant survival benefit from adjuvant chemotherapy for non–small-cell lung cancer (NSCLC). Whether elderly patients tolerate platinum-based adjuvant chemotherapy and derive the same survival advantage is unknown. This retrospective study evaluated the influence of age on survival, adjuvant chemotherapy delivery, and toxicity in National Cancer Institute of Canada (NCIC) Clinical Trials Group study JBR.10. Patients and Methods Pretreatment characteristics and survival were compared for 327 young (≤ 65 years) and 155 elderly (> 65 years) patients. Chemotherapy delivery and toxicity were compared for 213 treated patients (63 elderly, 150 young). Results Baseline demographics by age were similar with the exception of histology (adenocarcinoma: 58% young, 43% elderly; squamous: 32% young, 49% elderly; P = .001) and performance status (PS; PS 0: 53% young, 41% elderly; P = .01). Chemotherapy significantly prolonged overall survival for elderly patients (hazard ratio, 0.61; 95% CI, 0.38 to 0.98; P = .04). This benefit is similar to the effect for all patients in JBR.10. Mean dose-intensities of vinorelbine and cisplatin were 13.2 and 18.0 mg/m2/wk in young, respectively, and 9.9 and 14.1 mg/m2/wk in elderly patients (vinorelbine, P = .0004; cisplatin, P = .001), respectively. The elderly received significantly fewer doses of vinorelbine (P = .014) and cisplatin (P = .006). Fewer elderly patients completed treatment and more refused treatment (P = .03). There were no significant differences in toxicities, hospitalization, or treatment-related death by age group. Fifteen (11.9%) of 126 deaths in the young resulted from nonmalignant causes, and 15 (21.1%) of 71 in the elderly (P = .13). Conclusion Despite elderly patients’ receiving less chemotherapy, adjuvant vinorelbine and cisplatin improves survival in patients older than 65 years with acceptable toxicity. Adjuvant chemotherapy should not be withheld from elderly patients.
Etiology of Early-Onset Type 2 Diabetes in Indians: Islet Autoimmunity and Mutations in Hepatocyte Nuclear Factor 1α and Mitochondrial Gene
Authors: Sahu Ravi P. , Aggarwal Ajay , Zaidi Ghazala , Shah Ajay , Modi Kirti , Kongara Srikanth , Aggarwal Suraksha , Talwar Sudha , Chu Su , Bhatia Vijayalakshmi , Bhatia Eesh 
Published: April 2007

Abstract
Context: Indians are at high risk of developing type 2 diabetes mellitus (T2DM) at an early age, despite their lower body mass index. Studies on the etiology of patients presenting as early-onset T2DM in this racial group are not available.
Objective: The objective was to delineate the clinical features in young Indian patients with T2DM and to determine the role of mutations in the hepatocyte nuclear factor 1α (HNF1α) gene [MODY3 (maturity-onset diabetes of the young, type 3)], mitochondrial A3243G mutation, and islet autoimmunity in its etiology.
Design: This was an observational cohort study.
Setting: The setting was an outpatient diabetes clinic in a teaching hospital.
Patients: Ninety-six consecutive young patients with T2DM (onset, ≤30 yr) were included in the study.
Interventions: Glutamic acid decarboxylase and insulinoma antigen 2 antibodies, mitochondrial A3243G mutation, and the common HNF1α mutation P291fsinsC were measured in all patients. The entire HNF1α gene was studied for mutations in 32 subjects with onset less than 25 yr or with normal weight. The common HNF1α A98V polymorphism was studied in 91 patients.
Results: The patients were clinically heterogeneous, with 42% having a normal body mass index. Glutamic acid decarboxylase antibodies were present in three (3%) subjects and mitochondrial A3243G mutation in one (1%) subject. The P291fsinsC mutation was not detected in any patient. A MODY3 mutation (R200W) was detected in one patient (3%). In this family, diabetes cosegregated with the R200W mutation in the proband and his youngest brother but not in three paternal uncles. The Val 98 allele was associated with T2DM (allele frequency, 0.14 vs. 0.03 in controls; odds ratio, 5.2; P &lt; 0.001).
Conclusions: Despite a significant proportion of young Indian patients with T2DM having normal weight, islet autoimmunity, A3243G mitochondrial, and HNF1α gene mutations were infrequent.
Peptide Products of the Neurotrophin-Inducible Gene vgf Are Produced in Human Neuroendocrine Cells from Early Development and Increase in Hyperplasia and Neoplasia
Authors: Rindi Guido , Licini Lisa , Necchi Vittorio , Bottarelli Lorena , Campanini Nicoletta , Azzoni Cinzia , Favret Maurizio , Giordano Giovanna , D’Amato Filomena , Brancia Carla , Solcia Enrico , Ferri Gian-Luca 
Published: April 2007

Abstract
Background: Although the neurotrophin-inducible gene vgf is expressed in mammalian neurons and endocrine cells, limited data is available in man.
Aim: The objective of the study was to map proVGF peptides in human endocrine cells during development, adulthood, hyperplasia, and tumors.
Methods: Antisera were generated against peptides related to internal cleavage or cleavage-amidation sites (rat proVGF422–430 and human proVGF298–306-NH2) and the proVGF C-terminal ending (human proVGF607–615). Developing and normal adult endocrine cells, hyperplastic endocrine lesions (thyroid, parathyroid, lung, and stomach), and 120 tumors (102 endocrine) were studied. Immunogold electron microscopy was performed on normal adult pancreas and gut, and Western blotting was performed on extracts of control tissues and endocrine tumors.
Results: proVGF fragments were revealed in developing pituitary, gut, pancreas, and adrenal medulla from 10 gestational weeks, in normal adult pituitary and adrenal medulla, pancreatic glucagon, and insulin cells and gut serotonin cells, in hyperplastic thyroid calcitonin cells, lung P cells, gastric enterochromaffin-like cells, and gastrin cells, and in 88 of 102 endocrine tumors. At electron microscopy proVGF immunoreactivity was restricted to electron-dense granules. Western blotting revealed large molecular weight forms and cleavage fragments in both control tissues and tumor extracts.
Conclusions: proVGF-related peptides are present in endocrine cells early during development and adulthood and increase in hyperplasia and tumors, and proVGF fragments could be novel diagnostic tools for endocrine cells and related lesions, including tumors.
Cyclin-Dependent Kinase 5 Differentially Regulates the Transcriptional Activity of the Glucocorticoid Receptor through Phosphorylation: Clinical Implications for the Nervous System Response to Glucocorticoids and Stress
Authors: Kino Tomoshige , Ichijo Takamasa , Amin Niranjana D. , Kesavapany Sashi , Wang Yonghong , Kim Nancy , Rao Sandesh , Player Audrey , Zheng Ya-Li , Garabedian Michael J. , Kawasaki Ernest , Pant Harish C. , Chrousos George P. 
Published: April 2007

AbstractGlucocorticoids, major end effectors of the stress response, play an essential role in the homeostasis of the central nervous system and influence diverse functions of neuronal cells. We found that cyclin-dependent kinase 5 (CDK5), which plays important roles in the morphogenesis and functions of the nervous system and whose aberrant activation is associated with development of neurodegenerative disorders, interacted with the ligand-binding domain of the glucocorticoid receptor (GR) through its activator p35 or its active proteolytic fragment p25. CDK5 phosphorylated GR at multiple serines, including Ser203 and Ser211 of its N-terminal domain, and suppressed the transcriptional activity of this receptor on glucocorticoid-responsive promoters by attenuating attraction of transcriptional cofactors to DNA. In microarray analyses using rat cortical neuronal cells, the CDK5 inhibitor roscovitine differentially regulated the transcriptional activity of the GR on more than 90% of the endogenous glucocorticoid-responsive genes tested. Thus, CDK5 exerts some of its biological activities in neuronal cells through the GR, dynamically modulating GR transcriptional activity in a target promoter-dependent fashion.
Congenital Hypothyroidism, Dwarfism, and Hearing Impairment Caused by a Missense Mutation in the Mouse Dual Oxidase 2 Gene, Duox2
Authors: Johnson Kenneth R. , Marden Coleen C. , Ward-Bailey Patricia , Gagnon Leona H. , Bronson Roderick T. , Donahue Leah Rae 
Published: April 2007

Abstract
Dual oxidases generate the hydrogen peroxide needed by thyroid peroxidase for the incorporation of iodine into thyroglobulin, an essential step in thyroid hormone synthesis. Mutations in the human dual oxidase 2 gene, DUOX2, have been shown to underlie several cases of congenital hypothyroidism. We report here the first mouse Duox2 mutation, which provides a new genetic model for studying the specific function of DUOX2 in the thyroid gland and in other organ systems where it is hypothesized to play a role. We mapped the new spontaneous mouse mutation to chromosome 2 and identified it as a T&gt;G base pair change in exon 16 of Duox2. The mutation changes a highly conserved valine to glycine at amino acid position 674 (V674G) and was named “thyroid dyshormonogenesis” (symbol thyd) to signify a defect in thyroid hormone synthesis. Thyroid glands of mutant mice are goitrous and contain few normal follicles, and anterior pituitaries are dysplastic. Serum T4 in homozygotes is about one-tenth the level of controls and is accompanied by a more than 100-fold increase in TSH. The weight of adult mutant mice is approximately half that of littermate controls, and serum IGF-I is reduced. The cochleae of mutant mice exhibit abnormalities characteristic of hypothyroidism, including a delayed formation of the inner sulcus and tunnel of Corti and an abnormally thickened tectorial membrane. Hearing thresholds of adult mutant mice are on average 50–60 decibels (dB) above those of controls.
Marine current turbines: Pioneering the development of marine kinetic energy converters
Authors: Fraenkel P. L. 
Published: April 2007

This paper gives the rationale and background to an already advanced research and development (R&D) programme aimed at developing technology for the commercial exploitation of kinetic energy from marine currents. This is followed by a brief overview of the characteristics of the tidal stream resource, the technical principles by which it may be exploited, and the key technical challenges that need to be overcome. The paper includes a description of the pioneering ‘Seaflow’ Project involving the installation and testing, since May 2003, of a prototype 300 kW tidal turbine 3 km off Lynmouth. The next stage of Marine Current Turbines Ltd's R&D programme is then described: this involves the development of a 1 MW twin axial-flow rotor system, called ‘Seagen’ which is planned for installation early in 2007. The installation and testing of ‘Seagen’ will mark a landmark stage in the R&D programme because it will form the basis for the commercial technology to follow. A brief outline of future plans beyond ‘Seagen’ is also given.
Argatroban Anticoagulation in Critically III Patients
Authors: Beiderlinden Martin , Treschan Tanja A , Görlinger Klaus , Peters Jürgen 
Published: April 2007

Background: Despite long-term use of argatroban in clinical practice, no dosing recommendations exist for critically ill patients with multiple organ dysfunction (MODS) and suspected or proven heparin-induced thrombocytopenia (HIT). Objective: To determine the suitability of argatroban use in critically ill patients with MODS and HIT. Methods: We conducted prospective observation of 24 consecutive patients with suspected HIT who were being anticoagulated with argatroban (target activated partial thromboplastin time [aPTT] 1.5–2 times normal or 50–60 sec) using 2 μg/kg/min in the first 5 patients and 0.2 μg/kg/min in the subsequent 19 patients. Results: Infusion of argatroban 2 μg/kg/min over 4 hours caused bleeding complications in 3 patients as aPTT increased from 51 ± 18 to 86 ± 34 seconds (p = 0.02), prothrombin time (PT) decreased from 76 ± 27% to 33 ± 12% of normal reference values, and international normalized ratio (INR) increased from 1.4 ± 0.4 to 2.5 ± 0.9 (p = 0.007). Infusion of argatroban 0.2 μg/kg/min over 4 hours provided sufficient anticoagulation without bleeding complications. The aPTT in this population increased from 44 ± 9 to 59 ± 13 seconds (p < 0.001), and PT and INR remained unchanged (76 ± 22% and 69 ± 23% of normal reference values, 1.3 ± 0.3 and after 1.3 ± 0.3, respectively [p = 0.4]). Coagulation variables (aPTT, PT, INR) were significantly different between both dosing regimens after 4 hours of infusion (p = 0.042 and p = 0.003, respectively). The maintenance dose for target aPTT averaged 0.22 ± 0.15 μg/kg/min in both groups. Conclusions: In critically ill patients with MODS, argatroban 2 μg/kg/min, as recommended by the manufacturer, resulted in extensive anticoagulation. A tenfold lower starting dose is sufficient and safe for effective anticoagulation in this specific patient population.
Impact of a Pharmacy Resident on Hospital Length of Stay and Drug-Related Costs
Authors: Terceros Yvonne , Chahine-Chakhtoura Corinne , Malinowski Judith E , Rickley William F 
Published: April 2007

Background: The impact of pharmacy residents' interventions on medical rounds has not been well evaluated. Objective: To assess the impact of a resident's interventions on hospital length of stay, describe the types of interventions, and assess drug-related cost savings. Methods: Using a matched control design, we conducted an evaluative study of adults admitted to a general internal medicine unit over one month. The study group consisted of patients admitted to the service of a medical team that included a pharmacy resident and medical residents. The pharmacy resident prospectively collected data on patient demographics and interventions made during patient admission and follow-up rounds. The control group consisted of patients admitted to the service of a team consisting of medical residents only, over the same period. The medical records of the control group were retrospectively evaluated for potential interventions. Results: Forty patients were enrolled in each group (aged 63 ± 17 y, mean ± SD). In the study group, 250 of 271 interventions were accepted and fulfilled. In the control group, 321 potential interventions were identified. The mean length of stay of the study group was significantly lower than that of the control group (7.9 ± 7.2 days vs 10.9 ± 7.9 days, respectively; p = 0.008). In the study group and the control group, the total interventions were related to prescribing errors (51.3% vs 45.4%), preventable adverse drug events (32.9% vs 42.3%), patient monitoring (14% vs 7%), and drug interactions (1.8% vs 5.3%). In the study group, the net drug-related cost savings totaled $2087. Conclusions: Our study demonstrates the positive impact of a pharmacy resident on reducing the hospital length of stay and producing drug-related cost savings. Most interventions prevented adverse drug events and prescribing errors.
Processing of Reelin by Embryonic Neurons Is Important for Function in Tissue But Not in Dissociated Cultured Neurons
Authors: Jossin Yves , Gui Lanrun , Goffinet André M. 
Published: April 2007

Reelin, the protein defective in reeler mutant mice, plays a key role during brain development. Reelin is processed proteolytically at two sites, and the central fragment mimics functionin vitro.Here, we show that processing is functionally importantin vivo, a question that could not be addressed in our previous study. New monoclonal antibodies directed against central Reelin block its binding to lipoprotein receptors and perturb cortical developmentin vitro, confirming the importance of the central fragment that is detected in tissue and body fluids. Processing occurs when Reelin is incubated with embryonic neurons in culture or with their supernatant, but inhibition of processing by a metalloproteinase blocker does not prevent Reelin signaling in neurons. Furthermore, neurons internalize similarly full-length or central Reelin. In contrast, inhibition of processing prevents signaling and perturbs cortical development in cultured embryonic brain slices. Moreover,in vivo, the concentration of central Reelin is dramatically and selectively increased in receptor-deficient tissue, suggesting its specific downregulation after binding to receptors and internalization. We propose that processing by end-migration neurons is required in tissue (where Reelin is likely anchored to the extracellular matrix) to release the central fragment that diffuses locally and signals to target cells, whereas,in vitro, all Reelin forms have indiscriminate access to cells, so that cleavage is not necessary for signaling.