bluuebunny/crossref_metadata_2025 huggingface dataset:
Prognostic Role of Interleukin-1β Gene and Interleukin-1 Receptor Antagonist Gene Polymorphisms in Patients With Advanced Gastric Cancer
Authors: Graziano Francesco , Ruzzo Annamaria , Santini Daniele , Humar Bostjan , Tonini Giuseppe , Catalano Vincenzo , Berardi Rossana , Pizzagalli Francesca , Arduini Federica , Bearzi Italo , Scartozzi Mario , Cascinu Stefano , Testa Enrica , Ficarelli Rita , Magnani Mauro
Published: March 2005

Purpose

A high interleukin-1β (IL-1B) and interleukin-1 receptor antagonist (IL-RN) ratio underlies an unfavorable proinflammatory status. Also, it seems to be involved in the mechanisms of cancer cachexia and tumor angiogenesis and metastasis. Two single nucleotide polymorphisms in IL-1B gene (IL-1B-511C/T,IL-1B-31T/C) and a variable number of tandem repeat polymorphisms in IL-RN gene (IL-1RNlong/2) enhance the circulating levels of the two cytokines. The prognostic role of IL-1B/IL-1RN genotypes was investigated in patients with relapsed and metastatic gastric cancer treated with palliative chemotherapy.

Patients and Methods

Before starting palliative chemotherapy, 123 prospectively enrolled patients supplied peripheral-blood samples for DNA extraction. Survival data were analyzed according to IL-1RN/IL-1B genotypes.

Results

Forty-two patients showed wild-type genotypes (IL-1RNlong/long, IL-1B-511C/C, and IL-1B-31T/T; group A). Forty-five patients showed the IL-1RN2 polymorphism, with wild-type IL-1B genotypes in seven patients and with IL-1B-511C/T and/or IL-1B-31T/C polymorphisms in 38 patients (group B). The remaining 36 patients demonstrated wild-type IL-1RN, with IL-1B-511C/T and/or IL-1B-31T/C polymorphisms (group C). In group A and B patients, the median progression-free survival (PFS) was 25 and 26 weeks, respectively, and median overall survival (OS) was 42 and 43 weeks, respectively. Group C patients showed worse PFS (median, 16 weeks) and OS (median, 28 weeks) than group A (P = .006 for PFS; P = .0001 for OS) and group B patients (P = .01 for PFS; P = .0001 for OS). The long/T/C haplotype was overrepresented in patients with shortened PFS (P = .001) and OS (P = .0005).

Conclusion

In patients with advanced gastric cancer, IL-1B polymorphisms showed adverse prognostic influence when coupled with wild-type IL-1RN genotype. These findings deserve further investigation for potential anticancer activity of recombinant IL-RN.
Prognostic Significance of Allelic Imbalance at the c-kit Gene Locus and c-kit Overexpression by Immunohistochemistry in Pediatric Osteosarcomas
Authors: Entz-Werlé Natacha , Marcellin Luc , Gaub Marie-Pierre , Guerin Eric , Schneider Anne , Berard-Marec Perrine , Kalifa Chantal , Brugiere Laurence , Pacquement Helène , Schmitt Claudine , Tabone Marie-Dominique , Jeanne-Pasquier Corinne , Terrier Philippe , Dijoud Frédérique , Oudet Pierre , Lutz Patrick , Babin-Boilletot Annie
Published: March 2005

Purpose

Since the recent development of biologic agents targeting oncogenes, increasing attention has been focused on determining the role of tyrosine kinase receptors in the pathogenesis of tumors. Our study was designed to investigate the status of region 4q12, which contains the candidate gene c-kit, and the expression of c-kit by immunohistochemistry (IHC).

Patients and Methods

Paired blood and biopsy specimens of 68 children treated for high-grade primary osteosarcomas were collected. Microsatellite analysis at two genomic sites containing c-kit gene was performed on paired DNA using a sensible fluorescent polymerase chain reaction technology. To confirm the DNA data, we studied c-kit protein expression by IHC in 56 available paraffin-embedded tumor tissues.

Results

The frequency of allelic imbalance (AI) at locus 4q12 was 39% in the overall population. In agreement with previous studies, we did not detect microsatellite instability, allowing us to hypothesize that this pathway is not implicated. Furthermore, the normal status at locus 4q12 was associated with a significantly better survival in the whole osteosarcoma population (P = .05). IHC overexpression of c-kit was concordant in all cases presenting an AI. However, normal status at locus 4q12 was correlated to an absence of c-kit protein expression in 19 (65.5%) of 29 informative cases.

Conclusion

Allelotyping of locus 4q12, which contains the c-kit gene, could help pediatric osteosarcoma prognostic screening and showed a strong correlation with overexpression of c-kit protein. These results allowed us to hypothesize that, in some cases, a mutation of c-kit gene could lead to a protein overexpression.
Early Responses to Chemotherapy of Normal and Malignant Hematologic Cells Are Prognostic in Children With Acute Lymphoblastic Leukemia
Authors: Laughton Stephen J. , Ashton Lesley J. , Kwan Edward , Norris Murray D. , Haber Michelle , Marshall Glenn M.
Published: March 2005

Purpose

Improved cure rates for children with acute lymphoblastic leukemia (ALL) have resulted from better relapse prediction, using clinical and laboratory features at diagnosis, and more intensive therapy in high-risk patients. More recently, measurements of the variation in the response of malignant lymphoblasts to chemotherapy in vivo have further improved relapse prediction. It is unknown whether the variation in the response of nonmalignant hematologic cells after chemotherapy correlates with the response of lymphoblasts or risk of relapse.

Patients and Methods

We retrospectively evaluated myelosuppression during induction and consolidation chemotherapy in 227 children uniformly treated for ALL on consecutive Australian and New Zealand Children's Cancer Study Group protocols. The early response to treatment was assessed in a representative subset (n = 62) by determining minimal residual disease (MRD) level by molecular techniques on the end-of-induction bone marrow sample.

Results

We found that a slow rate of myeloid recovery at the end of induction chemotherapy, reflected in a low absolute neutrophil count (ANC), was highly predictive of relapse (P < .0001). Additionally, patients with a high end-of-induction MRD level had a high risk of relapse (P = .001). Multivariate analysis confirmed the independent prognostic significance of MRD and ANC at the end of induction chemotherapy (P < .05). There was no significant association between other measures of myelotoxicity and MRD or relapse.

Conclusion

We conclude that the responses of normal myeloid cells and malignant lymphoblasts to chemotherapy predict outcome by distinct mechanisms. While these results are promising, their use in the clinical setting needs to be examined in a future randomized controlled trial.
Effects of Parenteral Hydration in Terminally Ill Cancer Patients: A Preliminary Study
Authors: Bruera Eduardo , Sala Raul , Rico Maria Antonieta , Moyano Jairo , Centeno Carlos , Willey Jie , Palmer J. Lynn
Published: March 2005

Purpose

Most patients with cancer develop decreased oral intake and dehydration before death. This study aimed to determine the effect of parenteral hydration on overall symptom control in terminally ill cancer patients with dehydration.

Patients and Methods

Patients with clinical evidence of mild to moderate dehydration and a liquid oral intake less than 1,000 mL/day were randomly assigned to receive either parenteral hydration with 1,000 mL (treatment group) or placebo with 100 mL normal saline administered over 4 hours for 2 days. Patients were evaluated for target symptoms (hallucinations, myoclonus, fatigue, and sedation), global well-being, and overall benefit.

Results

Twenty-seven patients randomly assigned to the treatment group had improvement in 53 (73%) of their 73 target symptoms versus 33 (49%) of 67 target symptoms in the placebo group (n=22; P = .005). Fifteen (83%) of 18 and 15 (83%) of 18 patients had improved myoclonus and sedation after hydration versus eight (47%) of 17 and five (33%) of 15 patients after placebo (P = .035 and P = .005, respectively). There were no significant differences of improvement in hallucinations or fatigue between groups. When blinded to treatment, patients (17 [63%] of 77) and investigators (20 [74%] of 27) perceived hydration as effective compared with placebo in nine (41%) of 22 patients (P = .78) and 12 (54%) of 22 investigators (P = .15), respectively. The intensity of pain and swelling at the injection site were not significantly different between groups.

Conclusion

Parenteral hydration decreased symptoms of dehydration in terminally ill cancer patients who had decreased fluid intake. Hydration was well tolerated, and a placebo effect was observed. Studies with larger samples and a longer follow-up period are justified.
Effectiveness of Physical Activity on Cardiorespiratory Fitness and Health-Related Quality of Life in Young and Middle-Aged Cancer Patients Shortly After Chemotherapy
Authors: Thorsen Lene , Skovlund Eva , Strømme Sigmund B. , Hornslien Kjersti , Dahl Alv A. , Fosså Sophie D.
Published: March 2005

Purpose

To evaluate the effectiveness of a supervised home-based flexible training program on cardiorespiratory fitness (CRF), mental distress, and health-related quality of life (HRQOL) parameters in young and middle-aged cancer patients shortly after curative chemotherapy.

Patients and Methods

One hundred eleven patients age 18 to 50 years who had received chemotherapy for lymphomas or breast, gynecologic, or testicular cancer completed the trial. These patients were randomly allocated to either an intervention group (n = 59), which underwent a 14-week training program, or a control group (n = 52) that received standard care. Primary outcome was change in CRF, as determined by Åstrand-Rhyming indirect bicycle ergometer test (maximum oxygen uptake [VO2max]), between baseline (T0) and follow-up (T1). Secondary outcomes were mental distress, as assessed by the Hospital Anxiety and Depression Scale, and HRQOL, as assessed by the European Organisation for Research and Treatment of Cancer Core Quality of Life Questionnaire. Two-way analysis of covariance was used to analyze changes from T0 to T1.

Results

VO2max increased by 6.4 mL/kg–1/min–1 in patients in the intervention group and by 3.1 mL/kg–1/min–1 in patients in the control group (P < .01). The fatigue score decreased by 17.0 points in the control group compared with only 5.8 points in the intervention group (P < .01). There were no intergroup differences in mental distress or HRQOL.

Conclusion

A supervised, home-based, flexible training program has significant effect on CRF in young and middle-aged cancer patients shortly after curative chemotherapy, but it has no favorable effect on patients' experience of fatigue, mental distress, or HRQOL.
Risk of New Cancers After Radiotherapy in Long-Term Survivors of Retinoblastoma: An Extended Follow-Up
Authors: Kleinerman Ruth A. , Tucker Margaret A. , Tarone Robert E. , Abramson David H. , Seddon Johanna M. , Stovall Marilyn , Li Frederick P. , Fraumeni Joseph F.
Published: March 2005

Purpose

Many children diagnosed with retinoblastoma (Rb) survive into adulthood and are prone to subsequent cancers, particularly hereditary patients, who have germline Rb-1 mutations. We have extended the follow-up of a large cohort of Rb patients for 7 more years to provide new information on the risk of additional cancers after radiotherapy in long-term survivors.

Patients and Methods

We analyzed the risk of new cancers through 2000 in 1,601 Rb survivors, diagnosed from 1914 to 1984, at two US medical centers. The standardized incidence ratio (SIR) was calculated as the ratio of the observed number of cancers after hereditary and nonhereditary Rb to the expected number from the Connecticut Tumor Registry. The cumulative incidence of a new cancer after hereditary and nonhereditary Rb and radiotherapy was calculated with adjustment for competing risk of death.

Results

Subsequent cancer risk in 963 hereditary patients (SIR, 19; 95% CI, 16 to 21) exceeded the risk in 638 nonhereditary Rb patients (SIR, 1.2; 95% CI, 0.7 to 2.0). Radiation further increased the risk of another cancer in hereditary patients by 3.1-fold (95% CI, 2.0 to 5.3). Hereditary patients continued to be at significantly increased risk for sarcomas, melanoma, and cancers of the brain and nasal cavities. The cumulative incidence for developing a new cancer at 50 years after diagnosis of Rb was 36% (95% CI, 31% to 41%) for hereditary and 5.7% (95% CI, 2.4% to 11%) for nonhereditary patients.

Conclusion

Hereditary Rb predisposes to a variety of new cancers over time, with radiotherapy further enhancing the risk of tumors arising in the radiation field.
Study of Anxiety Disorder and Depression in Long-Term Survivors of Testicular Cancer
Authors: Dahl Alv A. , Haaland Carl Fredrik , Mykletun Arnstein , Bremnes Roy , Dahl Olav , Klepp Olbjørn , Wist Erik , Fosså Sophie D.
Published: March 2005

Purpose

To increase our knowledge of the prevalence of anxiety disorder and depression in long-term testicular cancer survivors (TCSs), and to identify variables associated with such caseness.

Patients and Methods

Participants were 1,408 TCSs treated between 1980 and 1994 in Norway. Participants provided information about their medical, social, and familial situation on a questionnaire. They also completed the Hospital Anxiety and Depression Scale (HADS). Anxiety disorder and depression were defined by a score ≥ 8 on the HADS subscales. The prevalence rates were compared with age-adjusted norm data.

Results

HADS-defined anxiety disorder was more prevalent in TCSs (19.2%; 95% CI, 17.2% to 21.3%) than in the norm sample (13.5%; 95% CI, 13.1% to 13.9%; P < .001), whereas the prevalence of HADS-defined depression did not differ from the norm (TCSs, 9.7%; 95% CI, 8.1% to 11.2% v norm, 10.1%, 95% CI, 9.5 to 10.5; P = .56). The relative risk for anxiety disorder was 1.49 (95% CI, 1.31 to 1.69) and for depression the relative risk was 0.96 (95% CI, 0.81 to1.14) in TCSs compared with norm. In multivariate analyses, HADS-defined anxiety disorder in TCSs was associated with young age, peripheral neuropathy, economic problems, alcohol problems, sexual problems, relapse anxiety, and having been treated for mental problems.

Conclusion

Long-term TCSs have an increased risk of HADS-defined anxiety disorder that warrants clinical attention. Checking easily available demographic and TC-related data and use of a simple screening test such as HADS assists the identification of TCSs with anxiety disorder.
Unequivocal Delineation of Clinicogenetic Subgroups and Development of a New Model for Improved Outcome Prediction in Neuroblastoma
Authors: Vandesompele Jo , Baudis Michael , De Preter Katleen , Van Roy Nadine , Ambros Peter , Bown Nick , Brinkschmidt Christian , Christiansen Holger , Combaret Valérie , Łastowska Maria , Nicholson James , O'Meara Anne , Plantaz Dominique , Stallings Raymond , Brichard Bénédicte , Van den Broecke Caroline , De Bie Sylvia , De Paepe Anne , Laureys Geneviève , Speleman Frank
Published: March 2005

Purpose

Neuroblastoma is a genetically heterogeneous pediatric tumor with a remarkably variable clinical behavior ranging from widely disseminated disease to spontaneous regression. In this study, we aimed for comprehensive genetic subgroup discovery and assessment of independent prognostic markers based on genome-wide aberrations detected by comparative genomic hybridization (CGH).

Materials and Methods

Published CGH data from 231 primary untreated neuroblastomas were converted to a digitized format suitable for global data mining, subgroup discovery, and multivariate survival analyses.

Results

In contrast to previous reports, which included only a few genetic parameters, we present here for the first time a strategy that allows unbiased evaluation of all genetic imbalances detected by CGH. The presented approach firmly established the existence of three different clinicogenetic subgroups and indicated that chromosome 17 status and tumor stage were the only independent significant predictors for patient outcome. Important new findings were: (1) a normal chromosome 17 status as a delineator of a subgroup of presumed favorable-stage tumors with highly increased risk; (2) the recognition of a survivor signature conferring 100% 5-year survival for stage 1, 2, and 4S tumors presenting with whole chromosome 17 gain; and (3) the identification of 3p deletion as a hallmark of older age at diagnosis.

Conclusion

We propose a new regression model for improved patient outcome prediction, incorporating tumor stage, chromosome 17, and amplification/deletion status. These findings may prove highly valuable with respect to more reliable risk assessment, evaluation of clinical results, and optimization of current treatment protocols.
Patients With an Unclassified Genetic Variant in the BRCA1 or BRCA2 Genes Show Different Clinical Features From Those With a Mutation
Authors: Gómez-García Encarna B. , Ambergen Ton , Blok Marinus J. , van den Wijngaard Arthur
Published: March 2005

Purpose

To obtain and compare the probabilities of finding a mutation in the BRCA1 or BRCA2 genes, the clinical features, and the family history among patients with an unclassified variant (UV) and those with a pathogenic mutation.

Patients and Methods

The study included 70 patients: 24 with a UV (BRCA1, n = 4; BRCA2, n = 19; both, n = 1), and 46 with a mutation (BRCA1, n = 32; BRCA2, n = 14). Two of the UVs were novel variants; the rest had been reported previously as UVs. Probabilities of finding a mutation were retrospectively obtained using BRCAPRO and Myriad II programs.

Results

The probability to detect a mutation was significantly lower in the group of patients with a UV than in those with a mutation (BRCAPRO [mean ± standard deviation], 0.297 ± 0.312 v 0.627 ± 0.315, P = .001; and Myriad II, 0.124 ± 0.090 v 0.283 ± 0.176, P = .001, respectively). Independent predictive factors of finding either a UV or a mutation were number of affected relatives (2.9 ± 1.4 v 4.0 ± 1.9; P = .039) and number of tumors among relatives (3.3 ± 1.4 v 4.4 ± 1.8; P = .031), respectively.

Conclusion

The combined data about the predictive models show significant differences between both groups. Individual probabilities can be regarded as a help to guide the clinical management of patients with a UV in those genes. However, a definitive conclusion about the pathogenicity of a UV can not be obtained from the clinical features alone, but only in combination with biochemical and epidemiologic data.
Primary CNS Lymphoma of T-Cell Origin: A Descriptive Analysis From the International Primary CNS Lymphoma Collaborative Group
Authors: Shenkier Tamara N. , Blay Jean-Yves , O’Neill Brian Patrick , Poortmans Philip , Thiel Eckhard , Jahnke Kristoph , Abrey Lauren E. , Neuwelt Edward , Tsang Richard , Batchelor Tracy , Harris Nancy , Ferreri Andrés J.M. , Ponzoni Maurilio , O’Brien Peter , Rubenstein James , Connors Joseph M.
Published: March 2005

Purpose

To describe the demographic and tumor related characteristics and outcomes for patients with primary T-cell CNS lymphoma (TPCNSL).

Patients and Methods

A retrospective series of patients with TPCNSL was compiled from twelve cancer centers in seven countries.

Results

We identified 45 patients with a median age of 60 years (range, 3 to 84 years). Twenty (44%) had Eastern Cooperative Oncology Group (ECOG) performance status (PS) of 0 or 1. Twenty-six (58%) had involvement of a cerebral hemisphere and sixteen (36%) had lesions of deeper sites in the brain. Serum lactate dehydrogenase was elevated in 7 (32%) of 22 patients, and CSF protein was elevated in 19 of 24 patients (79%) with available data. The median disease-specific survival (DSS) was 25 months (95% CI, 11 to 38 months). The 2- and 5-year DSS were 51% (95% CI, 35% to 66%) and 17% (95% CI, 6% to 34%), respectively. Univariate and multivariate analyses were conducted for age (≤ 60 v > 60 years), PS (0 or 1 v 2, 3, or 4), involvement of deep structures of the CNS (no v yes), and methotrexate (MTX) use in the primary treatment (yes v no). Only PS and MTX use were significantly associated with better outcome with hazard ratios of 0.2 (95% CI, 0.1 to 0.4) and 0.4 (95% CI, 0.2 to 0.8), respectively.

Conclusion

This is the largest series ever assembled of TPCNSL. The presentation and outcome appear similar to that of B cell PCNSL. PS 0 or 1 and administration of MTX are associated with better survival.
Randomized Trial of Amifostine in Locally Advanced Non–Small-Cell Lung Cancer Patients Receiving Chemotherapy and Hyperfractionated Radiation: Radiation Therapy Oncology Group Trial 98-01
Authors: Movsas Benjamin , Scott Charles , Langer Corey , Werner-Wasik Maria , Nicolaou Nicos , Komaki Ritsuko , Machtay Mitchell , Smith Colum , Axelrod Rita , Sarna Linda , Wasserman Todd , Byhardt Roger
Published: March 2005

Purpose

To test the ability of the cytoprotectant, amifostine, to reduce chemoradiotherapy-induced esophagitis and evaluate its influence on quality of life (QOL) and swallowing symptoms.

Patients and Methods

A total of 243 patients with stage II to IIIA/B non–small-cell lung cancer received induction paclitaxel 225 mg/m2 intravenously (IV) days 1 and 22 and carboplatin area under the curve (AUC) days 1 and 22, followed by concurrent weekly paclitaxel (50 mg/m2 IV) and carboplatin (AUC 2), and hyperfractionated radiation therapy (69.6 Gy at 1.2 Gy bid). Patients were randomly assigned at registration to amifostine (AM) 500 mg IV four times per week or no AM during chemoradiotherapy. Beyond standard toxicity end points, physician dysphagia logs (PDLs), daily patient swallowing diaries, and QOL (EORTC QLQ-C30/LC-13) were also collected. Swallowing AUC analyses were calculated from patient diaries and PDLs.

Results

A total of 120 patients were randomly assigned to receive AM, and 122, to receive no AM (one patient was ineligible); 72% received AM per protocol or with a minor deviation. AM was associated with higher rates of acute nausea (P = .03), vomiting (P = .007), cardiovascular toxicity (P = .0001), and infection or febrile neutropenia (P = .03). The rate of ≥ grade 3 esophagitis was 30% with AM versus 34% without AM (P = .9). Patient diaries demonstrated lower swallowing dysfunction AUC with amifostine (z test P = .025). QOL was not significantly different between the two arms, except for pain, which showed more clinically meaningful improvement and less deterioration at 6 weeks follow-up (v pretreatment) in the AM arm (P = .003). The median survival rates for both arms were comparable (AM, 17.3 v no AM, 17.9 months; P = .87).

Conclusion

AM did not significantly reduce esophagitis ≥ grade 3 in patients receiving hyperfractionated radiation and chemotherapy. However, patient self-assessments suggested a possible advantage to AM that is being explored with modified dosing route strategies.
Concurrent Administration of High-Dose Rituximab Before and After Autologous Stem-Cell Transplantation for Relapsed Aggressive B-Cell Non-Hodgkin’s Lymphomas
Authors: Khouri Issa F. , Saliba Rima M. , Hosing Chitra , Okoroji Grace-Julia , Acholonu Sandra , Anderlini Paolo , Couriel Daniel , De Lima Marcos , Donato Michele L. , Fayad Luis , Giralt Segio , Jones Roy , Korbling Martin , Maadani Farzaneh , Manning John T. , Pro Barbara , Shpall Elizabeth , Younes Anas , McLaughlin Peter , Champlin Richard E.
Published: March 2005

Purpose

We investigated the efficacy and safety of administering high-dose rituximab (HD-R) in combination with high-dose carmustine, cytarabine, etoposide, and melphalan chemotherapy and autologous stem-cell transplantation (SCT) in patients with recurrent B-cell aggressive non-Hodgkin’s lymphoma (NHL).

Patients and Methods

Sixty-seven consecutive patients were treated. Rituximab was administered during stem-cell mobilization (1 day before chemotherapy at 375 mg/m2 and 7 days after chemotherapy at 1,000 mg/m2), together with granulocyte colony-stimulating factor 10 μg/kg and granulocyte-macrophage colony-stimulating factor 250 μg/m2 administered subcutaneously daily. HD-R of 1,000 mg/m2 was administered again days 1 and 8 after transplantation. The results of this treatment were retrospectively compared with those of a historical control group receiving the same preparative regimen without rituximab.

Results

With a median follow-up time for the study group of 20 months, the overall survival rate at 2-years was 80% (95% CI, 65% to 89%) for the study group and 53% (95% CI, 34% to 69%) for the control group (P = .002). Disease-free survival was 67% (95% CI, 51% to 79%) for the study group and 43% (95% CI, 26% to 60%) for the control group (P = .004). The median time to recovery of absolute neutrophil count to ≥ 500 cells/μL was 11 days (range, 8 to 37 days) for the rituximab group and 10 days (range, 8 to 17 days) for the matched control group (P = .001). However, infections were not significantly increased in patients treated with rituximab.

Conclusion

The results of this study suggest that using HD-R and autologous SCT is a feasible and promising treatment for patients with B-cell aggressive NHL.
Arsenic Trioxide: New Clinical Experience With an Old Medication in Hematologic Malignancies
Authors: Douer Dan , Tallman Martin S.
Published: March 2005

Arsenic trioxide has shown great promise in the treatment of patients with relapsed or refractory acute promyelocytic leukemia (APL). In clinical trials, arsenic trioxide induces complete remission in 87% of patients and molecular remission in 83% of patients. Two-year overall and relapse-free survival estimates are 63% and 49%, respectively. Treatment with arsenic trioxide may be associated with the APL differentiation syndrome, leukocytosis, and electrocardiographic abnormalities. The expanded use of arsenic trioxide in APL for postremission therapy, in conjunction with transplantation, and in patients with newly diagnosed APL is under investigation. The multiple mechanisms of action of arsenic trioxide suggest that it may have antitumor activity in malignancies other than APL and that it may be used in combination with other agents to expand its potential use. This article reviews the clinical use of arsenic trioxide to date and discusses new therapeutic strategies evolving from its diverse biologic activities.
Endogenous Myc controls mammalian epidermal cell size, hyperproliferation, endoreplication and stem cell amplification
Authors: Zanet Jennifer , Pibre Sophie , Jacquet Chantal , Ramirez Angel , de Alborán Ignacio Moreno , Gandarillas Alberto
Published: March 2005

The transcription factor Myc (c-Myc) plays an important role in cell growth and cell death, yet its physiological function remains unclear. Ectopic activation of Myc has been recently suggested to regulate cell mass, and Drosophila dmyc controls cellular growth and size independently of cell division. By contrast, it has been proposed that in mammals Myc controls cell division and cell number. To gain insights into this debate we have specifically knocked out Myc in epidermis. Myc epidermal knockout mice are viable and their keratinocytes continue to cycle, but they display severe skin defects. The skin is tight and fragile, tears off in areas of mechanical friction and displays impaired wound healing. Steady-state epidermis is thinner, with loss of the proliferative compartment and premature differentiation. Remarkably, keratinocyte cell size, growth and endoreplication are reduced, and stem cell amplification is compromised. The results provide new and direct evidence for a role for endogenous Myc in cellular growth that is required for hyperproliferative cycles and tissue homeostasis.
Identification of the LEDGF/p75 HIV-1 integrase-interaction domain and NLS reveals NLS-independent chromatin tethering
Authors: Vanegas Maria , Llano Manuel , Delgado Sharon , Thompson Daniah , Peretz Mary , Poeschla Eric
Published: March 2005

To investigate the basis for the LEDGF/p75 dependence of HIV-1 integrase (IN) nuclear localization and chromatin association, we used cell lines made stably deficient in endogenous LEDGF/p75 by RNAi to analyze determinants of its location in cells and its ability to interact with IN. Deletion of C-terminal LEDGF/p75 residues 340-417 preserved nuclear and chromatin localization but abolished the interaction with IN and the tethering of IN to chromatin. Transfer of this IN-binding domain (IBD) was sufficient to confer HIV-1 IN interaction to GFP. HRP-2, the only other human protein with an identifiable IBD domain, was found to translocate IN to the nucleus of LEDGF/p75(–) cells. However, in contrast to LEDGF/p75, HRP-2 is not chromatin bound and does not tether IN to chromatin. A single classical nuclear localization signal (NLS) in the LEDGF/p75 N-terminal region (146RRGRKRKAEKQ156) was found by deletion mapping and was shown to be transferable to pyruvate kinase. Four central basic residues in the NLS are critical for its activity. Strikingly, however, stable expression studies with NLS(+/–) and IBD(+/–) mutants revealed that the NLS, although responsible for LEDGF/p75 nuclear import, is dispensable for stable, constitutive nuclear association of LEDGF/p75 and IN. Both wild-type LEDGF/p75 and NLS-mutant LEDGF/p75 remain entirely chromatin associated throughout the cell cycle, and each tethers IN to chromatin. Thus, these experiments reveal stable nuclear sequestration of a transcriptional regulator by chromatin during the nuclear-cytosolic mixing of cell division, which additionally enables stable tethering of IN to chromatin. LEDGF/p75 is a multidomain adaptor protein that interacts with the nuclear import apparatus, lentiviral IN proteins and chromatin by means of an NLS, an IBD and additional chromatin-interacting domains.
Assembly pathway of the anastralDrosophilaoocyte meiosis I spindle
Authors: Sköld Helén Nilsson , Komma Donald J. , Endow Sharyn A.
Published: March 2005

Oocyte meiotic spindles of many species are anastral and lack centrosomes to nucleate microtubules. Assembly of anastral spindles occurs by a pathway that differs from that of most mitotic spindles. Here we analyze assembly of the Drosophila oocyte meiosis I spindle and the role of the Nonclaret disjunctional (Ncd) motor in spindle assembly using wild-type and mutant Ncd fused to GFP. Unexpectedly, we observe motor-associated asters at germinal vesicle breakdown that migrate towards the condensed chromosomes, where they nucleate microtubules at the chromosomes. Newly nucleated microtubules are randomly oriented, then become organized around the bivalent chromosomes. We show that the meiotic spindle forms by lateral associations of microtubule-coated chromosomes into a bipolar spindle. Lateral interactions between microtubule-associated bivalent chromosomes may be mediated by microtubule crosslinking by the Ncd motor, based on analysis of fixed oocytes. We report here that spindle assembly occurs in an ncd mutant defective for microtubule motility, but lateral interactions between microtubule-coated chromosomes are unstable, indicating that Ncd movement along microtubules is needed to stabilize interactions between chromosomes. A more severe ncd mutant that probably lacks ATPase activity prevents formation of lateral interactions between chromosomes and causes defective microtubule elongation. Anastral Drosophila oocyte meiosis I spindle assembly thus involves motor-associated asters to nucleate microtubules and Ncd motor activity to form and stabilize interactions between microtubule-associated chromosomes during the assembly process. This is the first complete account of assembly of an anastral spindle and the specific steps that require Ncd motor activity, revealing new and unexpected features of the process.
Activation of either ERK1/2 or ERK5 MAP kinase pathways can lead to disruption of the actin cytoskeleton
Authors: Barros Joana Castro , Marshall Christopher J.
Published: March 2005

Oncogenic transformation often leads to the disruption of the actin cytoskeleton. Activation of the classical Ras-Raf-MEK1/2-ERK1/2 signalling cascade has been implicated in the effects of oncogenes such as Ras and Src on the cytoskeleton. Many of the studies of the effects of oncogenes on the cytoskeleton have made use of chemical inhibitors of MEK1/2 but it is now clear that these inhibitors also inactivate MEK5 in the MEK5-ERK5 MAP kinase pathway raising the possibility that this pathway may also be involved in oncogenic transformation. We therefore investigated whether activation of ERK5 can lead to disruption of the actin cytoskeleton. We show that activation of ERK5 can lead to loss of actin stress fibres, but by a distinct mechanism to ERK1/2. We demonstrate that ERK5 is activated by oncogenic Src as demonstrated by translocation of endogenous ERK5 from the cytoplasm to nucleus and activation of an ERK5-dependent transcriptional reporter and that ERK5 activation is required for Src-mediated transformation. We also show that in Src-transformed cells inhibition of ERK1/2 signalling is not sufficient for reappearance of the actin cytoskeleton and that ERK5 activation contributes to cytoskeletal disruption by Src. Our results suggest that multiple MAP kinase pathways downstream of oncogenes participate in cytoskeletal alterations.
Utility Green Pricing Programs: A Statistical Analysis of Program Effectiveness
Authors: Wiser Ryan , Olson Scott , Bird Lori , Swezey Blair
Published: March 2005

Utility green pricing programs represent one way in which consumers can voluntarily support the development of renewable energy. The design features and effectiveness of these programs varies considerably. Based on a survey of utility program managers in the United States, this article provides insight into which program features might help maximize both customer participation in green pricing programs and the amount of renewable energy purchased by customers in those programs. We find that program length has a substantial impact on customer participation and purchases; to achieve higher levels of success, utilities will need to remain committed to their product offering for some time. Our findings also suggest that utilities should consider higher renewable energy purchase thresholds for residential customers in order to maximize renewable energy sales. Smaller utilities are found to be more successful than larger utilities, and we find some evidence that providing private benefits to non-residential participants can enhance success. Interestingly, we find little evidence that the cost of the green pricing product greatly impacts customer participation and renewable energy sales, at least over the narrow range of premiums embedded in our data set, and for the initial set of green power purchasers.
Normative Science
Authors: Lackey Robert T.
Published: March 2005

Effectively resolving the typical fisheries policy issue requires providing an array of scientific information to decision-makers. In my experience, the ability of scientists (and scientific information) to constructively inform fisheries policy deliberations has been diminished when what is offered as “science” is inculcated with policy preferences. As with all human activity, the scientific enterprise is not free of values, nor is it objectively independent, but values reflected in subtle form as policy preferences should not be permitted to prejudice scientific information. Scientific information becomes “normative” when it contains tacit policy preferences and thus, by extension, promotes particular policy options. There are many examples of normative science corrupting the development of sound fisheries policy by operating under the guise of policy-neutral science. In fact, with its tacitly derived value and preference character, normative science provides little substantive help in reconciling the most divisive elements of fisheries policy. In my opinion, scientists should play the important role of “informing” fisheries policy discussions with unbiased, understandable scientific information, assessments, and forecasts. For developing sound fisheries policy, science is important, helpful, even essential, but involvement with policy issues by a naive scientist can lead to loss of credibility and perceived independence unless the proper roles of both science and policy are understood and followed.
The M&M Critique of the MBH98 Northern Hemisphere Climate Index: Update and Implications
Authors: McIntyre Stephen , McKitrick Ross
Published: March 2005

The differences between the results of McIntyre and McKitrick [2003] and Mann et al. [1998] can be reconciled by only two series: The Gaspé cedar ring width series and the first principal component (PC1) from the North American tree ring network. We show that in each case MBH98 methodology differed from what was stated in print and the differences resulted in lower early 15th century index values. In the case of the North American PC1, MBH98 modified the PC algorithm so that the calculation was no longer centered, but claimed that the calculation was “conventional”. The modification caused the PC1 to be dominated by a subset of bristlecone pine ring width series which are widely doubted to be reliable temperature proxies. In the case of the Gaspé cedars, MBH98 did not use archived data, but made an extrapolation, unique within the corpus of over 350 series, and misrepresented the start date of the series. The recent Corrigendum by Mann et al. denied that these differences between the stated methods and actual methods have any effect, a claim we show is false. We also refute the various arguments by Mann et al. purporting to salvage their reconstruction, including their claims of robustness and statistical skill. Finally, we comment on several policy issues arising from this controversy: the lack of consistent requirements for disclosure of data and methods in paleoclimate journals, and the need to recognize the limitations of journal peer review as a quality control standard when scientific studies are used for public policy.
Climate Change Policies in Norway and the Netherlands: Different Instruments, Similar Outcome?
Authors: Christiansen Atle Christer , Skjærseth Jon Birger
Published: March 2005

This paper examines the extent to which climate change policies and instruments in Norway and the Netherlands have provided continuous incentives for the development, adoption and diffusion of new abatement technologies. More specifically, the paper examines whether differences between the types of instruments adopted (Dutch voluntary agreements and the Norwegian CO2 tax), problem type and domestic political context have affected technological change in the two countries' petroleum sectors. In brief, empirical evidence suggests that the two cases display quite similar outcomes in terms of technological change. That said, there are also important differences, pertaining most notably to the development and adoption of radical innovations in the Norwegian petroleum sector. The differences are in turn attributed to the interplay between the respective policy instruments adopted and the political contexts in which they are applied. These findings are important not only for policymakers involved in the selection of effective instruments in climate change policy, but also for the development of theories and analytical frameworks to examine and assess dynamic efficiency.
Transport Energy Embodied in Consumer Goods: A Hybrid Life-Cycle Analysis
Authors: Munksgaard Jesper , Lenzen Manfred , Jensen Thomas C. , Pade Lise-Lotte
Published: March 2005

This paper describes an analysis of the transport-related energy embodied in goods consumed by households. Our approach combines bottom-up with top-down modelling in a hybrid life-cycle analysis. The bottom-up part is a process analysis of international transport, examining foreign trade statistics, transportation modes, transport distances, and energy efficiencies. The top-down part is an input-output analysis identifying transport energy use in upstream production layers. To demonstrate the application of the model we carry out a three-step empirical analysis of goods consumed in Denmark in 1995, starting with highly aggregated commodity groups, and ending with “bread”.
Update on Personal Digital Assistant Applications for the Healthcare Provider
Authors: Keplar Kristine E , Urbanski Christopher J , Kania Deanna S
Published: March 2005

OBJECTIVE:

To review the common general drug information applications and specialty drug information applications available for personal digital assistants (PDAs).

DATA SOURCES:

The literature was accessed through MEDLINE (2003–June 2004). Other information was obtained through secondary sources, such as Web sites describing common PDA applications as well as actual product trials. The key search terms used were handheld, PDA, personal digital assistants, drug information, pharmacokinetics, medical information, and medical applications.

STUDY SELECTION AND DATA EXTRACTION:

Articles or studies that provided a review of drug information references for the PDA since 2002 were included. Data pertaining to cost and application size were obtained from product or vendor Web sites.

DATA SYNTHESIS:

There are numerous medical applications available for the PDA including general drug information references, specialty drug information references (eg, pediatrics, cardiology, infectious diseases, oncology, psychology, herbals), diagnostic applications, medical calculators, nursing references, and patient tracking databases. Due to the huge array of programs, as well as factors such as cost and memory requirements, the healthcare provider must be selective in the medical applications that are placed on the PDA.

CONCLUSIONS:

There are many excellent PDA drug information applications that provide fast and accurate drug information and other features that assist the healthcare provider.
Efficacy of Topical Anesthetics to Reduce Pain in Premature Infants during Eye Examinations for Retinopathy of Prematurity
Authors: Marsh Virginia A , Young William O , Dunaway Kimberly K , Kissling Grace E , Carlos Rita Q , Jones Susan M , Shockley Dawn H , Weaver Nicole L , Ransom J Laurence , Gal Peter
Published: March 2005

BACKGROUND:

Eye examinations for retinopathy of prematurity (ROP) are stressful and probably painful, but many ophthalmologists do not apply topical anesthetics because their efficacy in reducing pain has not been established.

OBJECTIVE:

To evaluate the potential benefits of topical anesthetic eye drops in reducing pain during neonatal eye examination for ROP.

METHODS:

Neonates born at ⩽30 weeks' gestation and expected to have at least 2 examinations for ROP were included. Patients were randomly assigned to receive either proparacaine HCl ophthalmic solution 0.5% or NaCl 0.9% (saline) eye drops prior to an eye examination. In a subsequent examination, each patient received the alternate treatment. Eye drops were prepared in the pharmacy in identical tuberculin syringes, and physicians, nurses, and pharmacists were blinded to the treatment given. Pain was measured using a scoring system with both physical and physiologic measures of pain (Premature Infant Pain Profile [PIPP], possible range 1–21), which has been validated in preterm infants. PIPP scoring was performed simultaneously by 2 nurses: 1 and 5 minutes before and after the eye examination and during initial placement of the eye speculum. The same ophthalmologist performed all examinations.

RESULTS:

Twenty-two patients were studied, with 11 infants receiving proparacaine and 11 receiving saline as the first treatment. Crossover was performed with a median of 17.5 days between treatments. Patients experienced significantly less pain at speculum insertion with proparacaine than with saline (paired difference −2.5 ± 3.4; p = 0.001).

CONCLUSIONS:

Topical anesthetic pretreatment reduces the pain response to eye examination for ROP and should become routine practice. Because this is not effective in all infants, additional measures to reduce pain should be taken.
Molecular Determinants for Modulation of Persistent Sodium Current by G-Protein βγ Subunits
Authors: Mantegazza Massimo , Yu Frank H. , Powell Andrew J. , Clare Jeffrey J. , Catterall William A. , Scheuer Todd
Published: March 2005

Voltage-gated sodium channels are responsible for the upstroke of the action potential in most excitable cells, and their fast inactivation is essential for controlling electrical signaling. In addition, a noninactivating, persistent component of sodium current,INaP, has been implicated in integrative functions of neurons including threshold for firing, neuronal bursting, and signal integration. G-protein βγ subunits increaseINaP, but the sodium channel subtypes that conductINaPand the target site(s) on the sodium channel molecule required for modulation by Gβγ are poorly defined. Here, we show thatINaPconducted by Nav1.1 and Nav1.2 channels (Nav1.1 > Nav1.2) is modulated by Gβγ; Nav1.4 and Nav1.5 channels produce smallerINaPthat is not regulated by Gβγ. These qualitative differences in modulation by Gβγ are determined by the transmembrane body of the sodium channels rather than their cytoplasmic C-terminal domains, which have been implicated previously in modulation by Gβγ. However, the C-terminal domains determine the quantitative extent of modulation of Nav1.2 channels by Gβγ. Studies of chimeric and truncated Nav1.2 channels identify molecular determinants that affect modulation ofINaPlocated between amino acid residue 1890 and the C terminus at residue 2005. The last 28 amino acid residues of the C terminus are sufficient to support modulation by Gβγ when attached to the proximal C-terminal domain. Our results further define the sodium channel subtypes that generateINaPand identify crucial molecular determinants in the C-terminal domain required for modulation by Gβγ when attached to the transmembrane body of a responsive sodium channel.
AMPA/Kainate Receptor-Mediated Downregulation of GABAergic Synaptic Transmission by Calcineurin after Seizures in the Developing Rat Brain
Authors: Sanchez Russell M. , Dai Weimin , Levada Rachel E. , Lippman Jocelyn J. , Jensen Frances E.
Published: March 2005

Hypoxia is the most common cause of perinatal seizures and can be refractory to conventional anticonvulsant drugs, suggesting an age-specific form of epileptogenesis. A model of hypoxia-induced seizures in immature rats reveals that seizures result in immediate activation of the phosphatase calcineurin (CaN) in area CA1 of hippocampus. After seizures, CA1 pyramidal neurons exhibit a downregulation of GABAAreceptor (GABAAR)-mediated inhibition that was reversed by CaN inhibitors. CaN activation appears to be dependent on seizure-induced activation of Ca2+-permeable AMPA receptors (AMPARs), because the upregulation of CaN activation and GABAAR inhibition were attenuated by GYKI 52466 [1-(4-aminophenyl)-4-methyl-7,8-methylenedioxy-5H-2,3-benzodiazepine hydrochloride] or Joro spider toxin. GABAAR β2/3 subunit protein was dephosphorylated at 1 h after seizures, suggesting this subunit as a possible substrate of CaN in this model. Finally,in vivoadministration of the CaN inhibitor FK-506 significantly suppressed hypoxic seizures, and posttreatment with NBQX (2,3-dihydroxy-6-nitro-7-sulfonyl-benzo[f]quinoxaline) or FK-506 blocked the hypoxic seizure-induced increase in CaN expression. These data suggest that Ca2+-permeable AMPARs and CaN regulate inhibitory synaptic transmission in a novel plasticity pathway that may play a role in epileptogenesis in the immature brain.