bluuebunny/crossref_metadata_2025 huggingface dataset:
In vitro and in vivo enzyme studies of polyhemoglobin‐tyrosinase
Authors: Yu B. , Chang T.M.S.
Published: May 2004

Melanoma is now the fifth most common type of cancer in North America. At present, there is no optimal treatment for this cancer. However, the lowering of the tyrosine level can inhibit the growth of melanoma. Unfortunately, this diet restriction cannot be humanly tolerated and causes vomiting, nausea, and severe body weight loss. To prevent these problems, we are studying a new approach involving the preparation intermolecularly crosslinked hemoglobin and tyrosinase for intravenous injection. In this article we describe the method of preparation and the structural and functional properties of polyhemoglobin‐tyrosinase. We evaluate the effects of varying glutaraldehyde ratio, crosslinking time, and enzyme concentration on the enzyme activity of polyhemoglobin‐tyrosinase. We also optimize the molecular weight distribution of polyhemoglobin‐tyrosinase. The stability of polyhemoglobin‐tyrosinase at 37°C is much more stable when compared to noncrosslinked tyrosinase solution. Animal studies show that a higher degree of polymerization correlates with a longer circulation time of polyhemoglobin‐tyrosinase, and the optimal crosslinking time is 24 hours. One intravenous injection of polyhemoglobin‐tyrosinase lowers the plasma tyrosine to about 10% of its original level within one hour. © 2004 Wiley Periodicals, Inc.
Effect of ethanol, acetate, and phenol on toluene degradation activity and tod–lux expression in Pseudomonas putida TOD102: evaluation of the metabolic flux dilution model
Authors: Lovanh Nanh , Alvarez Pedro J. J.
Published: May 2004

The reporter strain Pseudomonas putida TOD102 (with a tod‐lux fusion) was used in chemostat experiments with binary substrate mixtures to investigate the effect of potentially occurring cosubstrates on toluene degradation activity. Although toluene was simultaneously utilized with other cosubstrates, its metabolic flux (defined as the toluene utilization rate per cell) decreased with increasing influent concentrations of ethanol, acetate, or phenol. Three inhibitory mechanisms were considered to explain these trends: (1) repression of the tod gene (coding for toluene dioxygenase) by acetate and ethanol, which was quantified by a decrease in specific bioluminescence; (2) competitive inhibition of toluene dioxygenase by phenol; and (3) metabolic flux dilution (MFD) by all three cosubstrates. Based on experimental observations, MFD was modeled without any fitting parameters by assuming that the metabolic flux of a substrate in a mixture is proportional to its relative availability (expressed as a fraction of the influent total organic carbon). Thus, increasing concentrations of alternative carbon sources “dilute” the metabolic flux of toluene without necessarily repressing tod, as observed with phenol (a known tod inducer). For all cosubstrates, the MFD model slightly overpredicted the measured toluene metabolic flux. Incorporating catabolite repression (for experiments with acetate or ethanol) or competitive inhibition (for experiments with phenol) with independently obtained parameters resulted in more accurate fits of the observed decrease in toluene metabolic flux with increasing cosubstrate concentration. These results imply that alternative carbon sources (including inducers) are likely to hinder toluene utilization per unit cell, and that these effects can be accurately predicted with simple mathematical models. © 2004 Wiley Periodicals, Inc.
How issues get framed and reframed when different communities meet: a multi‐level analysis of a collaborative soil conservation initiative in the Ecuadorian Andes
Authors: Dewulf Art , Craps Marc , Dercon Gerd
Published: May 2004

Drawing on qualitative data from a longitudinal case study of a collaborative soil conservation initiative in southern Ecuador, we study how multiple actors, including university experts, development organizations and local communities, make sense of the issues from different perspectives through the process of issue framing. Starting from an analysis of the actors' usual issue frames, we point out their differences in selecting aspects, connecting them and drawing boundaries around the issues. Bringing in the time dimension leads us to consider how changing patterns of actor involvement and evolving frame configurations mutually influence each other. In a third step, we zoom in on the here‐and‐now level of ongoing interaction using discourse analysis, outlining an interactive, communicative and discursive approach to dealing with differences in issue framing. We identify various ways of dealing with these differences and argue that approaching them constructively by tuning the different frames into a mutually acceptable configuration is an important challenge for any attempt at integrated management of natural resources. Copyright © 2004 John Wiley & Sons, Ltd.
Strong opposition: frame‐based resistance to collaboration
Authors: Gray Barbara
Published: May 2004

While many studies of collaboration have relied on processual factors to explain outcomes of conflicts among the stakeholders, the failure of collaboration can also be explained by the divergence of stakeholders' frames about the issues. Research on environmental conflicts has shown that the ways in which the stakeholders frame the issues and the conflict itself explain collaborative success or failure. When stakeholders' frames about the issues, the process of their interaction, and about each other are vastly different, collaboration to find an agreeable solution becomes exceedingly difficult. In this article I present a case study of a protracted conflict over Voyageurs National Park in northern Minnesota (USA) to show how frames impeded the stakeholders from finding a collaborative solution to the conflict despite an 18‐month mediation effort. How the stakeholders construed their own identities in the conflict, how they constructed the problems or opportunities that linked them, as well as the frames they held about how the conflict should be resolved, all worked to prevent collaboration. Consequently, stakeholders' frames and processes for promoting reframing are critical to understanding how collaborative partnerships evolve and whether they will eventually succeed or fail. Copyright © 2004 John Wiley & Sons, Ltd.
Processes of social learning in integrated resources management
Authors: Pahl‐Wostl Claudia , Hare Matt
Published: May 2004

In recent years the human dimension and governance issues have gained more and more in importance in the management of natural resources. One important aspect is to understand the processes of social learning that precede any collective decision‐making.

The HarmoniCOP project developed a framework for social learning for resources management that can be interpreted as combining content management as well as social involvement processes to achieve both technical and relational outcomes.

Social learning was taken into account in a new approach called participatory agent based social simulation. Participatory agent based social simulation deviates in a number of ways from conventional modelling. The actors themselves whose behaviour is represented in the model and who are supposed to later use the models for decision‐making and strategic planning, participate and contribute to the modelling process. Models serve as tools of communication in processes of social learning.

This article reports on a Swiss case study which dealt with the development of new management strategies for urban water management. It will provide examples of how different techniques can be used to establish a process of social learning within a long‐term participatory management project using participatory agent‐based social simulation. Social learning is highlighted as important for management regimes that require changes in social practices, roles and responsibilities. Copyright © 2004 John Wiley & Sons, Ltd.
Paradox of participation: giving or taking part?
Authors: Quaghebeur Kerlijn , Masschelein Jan , Nguyen Hoai Huong
Published: May 2004

In this article we address our experiences with a so‐called participatory approach in a Vietnamese‐Belgian water management project. This project aimed, in its social science component, at stimulating and studying processes of reflexive social learning and of participation and negotiation on local water management issues and on project activities. In this article we intend to show how specific project‐related strategies and attempts towards facilitating participation fail and how other initiatives seem to succeed or at least to elicit valuable processes of negotiation and learning. We start from the commonly held view on participation as committed to reverse or subvert power relations. However, our research experiences indicate that participation is always part of an operation of power, governing people to behave themselves in a particular determined way. From this Foucauldian governmental perspective, we are able to reconsider the success and failure of participatory approaches, not so much in terms of the effectiveness of their application, but rather in terms of the possibility to refuse ‘participatory’ government. Copyright © 2004 John Wiley & Sons, Ltd.
Multi‐party collaboration as social learning for interdependence: developing relational knowing for sustainable natural resource management
Authors: Bouwen René , Taillieu Tharsi
Published: May 2004

This article develops a conceptual framework to theorize about and to intervene in multi‐party collaboration projects related to natural resource issues. It is a recent trend in public and private interorganizational policy that multiple actors get involved to collaborate around issues of water and soil management, nature preservation, land use, farming practices, introduction of new technologies in life sciences and related problem domains. Awareness grows that blue print planning‐ implementation approaches are no longer sufficient to obtain viable and sustainable outcomes. The technical complexity and social embeddedness of these issues, require the collaboration of public authorities, private business, scientific experts, groups of users and social interest groups, non‐governmental organizations and representatives of stakeholders in the particular ecological domain. The central concern is always an interdependent involvement of the stakeholders, the development of a shared problem definition, the coordination of the different actions on all levels and the orientation towards a shared common script and action strategy. Social psychology and particularly organizational psychology, building on theories of interorganizational collaboration and social and organizational development, are challenged to make a contribution here. The different stakeholders engage in joint practices where the acknowledgement and the development of viable interdependencies are at stake. Learning about those interdependencies is considered in this article as the critical constitutive process and form of these multi‐party projects. Through sharing problem perspectives and working with different kinds of knowledge and competencies, multiple actors or stakeholder parties co‐construct a social learning process in an emerging community of practice. Copyright © 2004 John Wiley & Sons, Ltd.
Consensus conference on genetic testing: citizenship and technology
Authors: Vandenabeele Joke , Goorden Lieve
Published: May 2004

What is the process to be facilitated when citizens get the opportunity to make their voices heard in the debate on biotechnology? We observed the challenges citizens take up when participating in a ‘Consensus Conference’ on Genetic Testing and analysed the ambivalences of the learning process. Facilitators, not only should guide the interaction process, but also should support the substance of the process, that is an interaction between personal stories of citizens, the questions that spring from it and the knowledge of experts. Copyright © 2004 John Wiley & Sons, Ltd.
The effects of the caffeic acid phenethyl ester (CAPE) on erythrocyte membrane damage after hind limb ischaemia–reperfusion
Authors: Tamer Lülüfer , Sucu Nehir , Ercan Bahadır , Ünlü Ali , Çalıkoğlu Mukadder , Bilgin Ramazan , Değirmenci Ulaş , Atik Uğur
Published: May 2004

Reactive oxygen species have been implicated in pathogenesis injury after ischaemia–reperfusion (I/R). Caffeic Acid Phenethyl Ester (CAPE), an active component of honeybee propolis extract, exhibits antioxidant and anti‐inflammatory properties. The aim of this study was to investigate the effects of CAPE on erythrocyte membrane damage after hind limb I/R. Rats were divided into two groups: I/R and I/R with CAPE pre‐treatment. They were anaesthetized with intramuscular ketamine 100 mg kg−1. A 4‐h I/R period was performed on the right hind limb of all animals. In the CAPE‐treated group, animals received CAPE 10 μm by intraperitoneal injection 1 h before the reperfusion. At the end of the reperfusion period, a midsternotomy was performed. A 5‐ml blood sample was withdrawn from the ascending aorta for biochemical assays. Serum and erythrocyte membrane MDA levels were significantly lower in the CAPE‐treated group when compared to the I/R group ( p = 0.001 and p<0.001, respectively). Erythrocyte membrane Na+‐K+ ATPases activity in the CAPE‐treated group was significantly higher than the I/R group ( p<0.001). In conclusion, CAPE seems to be effective in protecting against oxidative stress. Therefore, we suggest that in order to decrease I/R injury, pre‐administration of CAPE may be a promising agent for a variety of conditions associated with I/R. Copyright © 2004 John Wiley & Sons, Ltd.
First‐order perturbation analysis of the best rank‐(R1, R2, R3) approximation in multilinear algebra
Authors: De Lathauwer Lieven
Published: May 2004

In this paper we perform a first‐order perturbation analysis of the least squares approximation of a given higher‐order tensor by a tensor having prespecified n‐mode ranks. This work generalizes the classical first‐order perturbation analysis of the matrix singular value decomposition. We will show that there are important differences between the matrix and the higher‐order tensor case. We subsequently address (1) the best rank‐1 approximation of supersymmetric tensors, (2) the best rank‐(R1, R2, R3) approximation of arbitrary tensors and (3) the best rank‐(R1, R2, R3) approximation of arbitrary tensors. Copyright © 2004 John Wiley & Sons, Ltd.
Partial uniqueness in CANDECOMP/PARAFAC
Authors: ten Berge Jos M. F.
Published: May 2004

A key property of CANDECOMP/PARAFAC is the essential uniqueness it displays under certain conditions. It has been known for a long time that, when these conditions are not met, partial uniqueness may remain. Whereas considerable progress has been made in the study of conditions for uniqueness, the study of partial uniqueness has lagged behind. The only well known cases are those of overfactoring, when more components are extracted than are required for perfect fit, and those cases where the data do not have enough system variation, resulting in proportional components for one or more modes. The present paper deals with partial uniqueness in cases where the smallest number of components is extracted that yield perfect fit. For the case of K×K×2 arrays of rank K, randomly sampled from a continuous distribution, it is shown that partial uniqueness, with some components unique and others differing between solutions, arises with probability zero. Also, a closed‐form CANDECOMP/PARAFAC solution is derived for 5×3×3 arrays when these happen to have rank 5. In such cases, any two different solutions share four of the five components. This phenomenon will be traced back to a sixth degree polynomial having six real roots, any five of which can be picked to construct a solution. Copyright © 2004 John Wiley & Sons, Ltd.
Weak Hydrogen Bridges: A Systematic Theoretical Study on the Nature and Strength of CH⋅⋅⋅FC Interactions
Authors: Hyla‐Kryspin Isabella , Haufe Günter , Grimme Stefan
Published: May 2004

We present a comparative study on the nature and strength of weak hydrogen bonding between the C(sp3)H , C(sp2)H, and C(sp)H donor bonds and FC(sp3) acceptors. The series of molecules CH3F⋅CH4(2 a,2 b), CH3F⋅C2H4(3), CH3F⋅C2H2(4), as well as model complexes of experimentally characterized 2‐fluoro‐2‐phenylcyclopropane derivatives, C3H6⋅C3H5F (5 a,5 b) and C3H5F⋅C3H5F (6) were investigated. Comparative studies were also performed for two conformers of the methane dimer (1 a,1 b). The calculations were carried out in hierarchies of basis sets [SV(d,p), TZV(d,p), aug‐TZV(d,p), TZV(2df,2pd), aug‐TZV(2df,2pd), QZV(3d2fg,2pd), aug‐QZV(3d2fg,2pdf)] by means of ab initio [HF, MP2, QCISD, QCISD(T)] methods and density functional theory (DFT/B3LYP, DFT/PBE). It is shown that well‐balanced basis sets of at least TZV(2df,2pd) quality are needed for a proper description of the weakly bonded systems. In the case of2,3,5, and6, the dispersion interaction is the dominant term of the entire attraction, which is not accounted for at the B3LYP level. Significant electrostatic contributions are observed for6and3. For4, these forces have a dominating contribution to the hydrogen bonding. The C(sp)H⋅⋅⋅FC(sp3) interaction in4, though weak, exhibits the same characteristics as conventional hydrogen bridges. Despite showing longer H⋅⋅⋅F/H contacts compared to1 a,2 a, and5 athe bifurcated structures,1 b,2 b,5 b, are characterized by larger dispersion interactions leading to stronger bonding. For the systems with only one H⋅⋅⋅F contact, the MP2/QZV(3d2fg,2pd) interaction energy increases in the order2 a(−1.62 kJ mol−1),3(−2.79 kJ mol−1),5 a(−5.97 kJ mol−1),4(−7.25 kJ mol−1), and6(−10.02 kJ mol−1). This contradicts the estimated proton donor ability of the CH bonds (2 a<5 a<3<6<4).
Cover Picture: Multi‐Step Application of Immobilized Reagents and Scavengers: A Total Synthesis of Epothilone C (Chem. Eur. J. 10/2004)
Authors: Storer R. Ian , Takemoto Toshiyasu , Jackson Philip S. , Brown Dearg S. , Baxendale Ian R. , Ley Steven V.
Published: May 2004

The cover picture, created by Doug Scard, offers a look over the tubulin horizon, depicting the bringing together of ingredients, solid‐supported reagents and scavengers to produce the anti‐tumour compound Epothilone C. Rather like a fine wine, the unwanted residues may be removed by filtration. For more information see the article by S. V. Ley et al. on p. 2529 ff.
Increasing the dosage of vincristine
Authors: Kellie Stewart J. , Koopmans Pauline , Earl John , Nath Christa , Roebuck Derek , Uges Donald R. A. , de Graaf Siebold S. N.
Published: May 2004

BACKGROUND

Vincristine (VCR) is widely used to treat patients with malignant disease; among the patients treated with VCR are children with brain tumors. In vitro studies have demonstrated that the cytotoxic activity of VCR is related to both extracellular concentration and duration of exposure. The attainment of higher plasma concentrations by injecting larger bolus doses of VCR has been limited by concerns about neurotoxicity. One possible alternative strategy for enhancing the antitumor efficacy of VCR involves prolonging the duration of in vivo exposure. Therefore, the authors explored the neurotoxicity and pharmacokinetics of VCR administered via a 96‐hour continuous infusion after administration of a conventional bolus dose in a pediatric population.

METHODS

The current study included 16 patients, 11 of whom were males. The median age of the study population was 4.8 years (range, 1.7–15.8 years). The diagnoses included intrinsic pontine glioma (n = 4), ependymoma (n = 5), astrocytoma (n = 3), medulloblastoma/primitive neuroectodermal tumor (PNET; n = 2), ganglioglioma (n = 1), and choroid plexus carcinoma (n = 1). Of the 16 patients, 5 were newly diagnosed, and the remaining 11 had disease recurrences, 8 of which arose after radiotherapy. Treatment included cyclophosphamide 65 mg/kg administered intravenously over 1 hour on Day 1, a bolus of VCR 1.5 mg/m2 administered intravenously on Day 2, and VCR 0.5 mg/m2 per 24 hours administered via continuous intravenous infusion on Days 2–5. Thus, a total VCR dose of 3.5 mg/m2 was administered via infusion over 4 days. Fifteen patients received 2 courses of treatment at 21–28‐day intervals, and a total of 31 treatment courses were administered. VCR concentrations in plasma samples were measured using high‐performance liquid chromatography.

RESULTS

Jaw pain, constipation, mild abdominal pain, and depressed reflexes were common. However, only 1 of 31 courses was associated with Grade III toxicity, and no Grade IV toxicity (e.g., cranial nerve palsy, ileus, inappropriate antidiuretic hormone secretion, seizures, hallucinations, etc.) was noted. The steady‐state plasma concentration of VCR during continuous infusion ranged from 1 to 3 μg/L in all patients. Responses after 2 courses were evaluated in 14 of 16 patients. A complete response was noted in one patient (astrocytoma), a partial response in three patients (one each with astrocytoma, ependymoma, and PNET), stable disease in seven patients, and disease progression in three patients.

CONCLUSIONS

Continuous infusion of VCR after a conventional bolus dose plus cyclophosphamide for children with tumors of the central nervous system did not result in significant neurotoxicity and appeared to be a safe strategy for achieving increased systemic exposure. Cancer 2004. © 2004 American Cancer Society.
Granulocyte–colony‐stimulating factor (filgrastim) may overcome imatinib‐induced neutropenia in patients with chronic‐phase chronic myelogenous leukemia
Authors: Quintas‐Cardama Alfonso , Kantarjian Hagop , O'Brien Susan , Garcia‐Manero Guillermo , Rios Mary B. , Talpaz Moshe , Cortes Jorge
Published: May 2004

BACKGROUND

Imatinib mesylate administration has become standard treatment for patients with chronic myelogenous leukemia (CML). Although the safety profile of imatinib is favorable, Grade ≥ 3 neutropenia (according to the National Cancer Institute Common Toxicity Criteria) occurs in 35–45% of patients with CML in chronic phase who receive standard‐dose imatinib. Myelosuppression results in treatment interruptions, which may compromise responses to imatinib. The authors investigated the ability of granulocyte–colony‐stimulating factor (filgrastim) to reverse imatinib‐associated neutropenia, thereby allowing for more continuous imatinib administration.

METHODS

Thirteen patients with chronic‐phase CML and Grade ≥ 3, imatinib‐induced neutropenia were treated with filgrastim. Treatment with filgrastim was initiated after a median of 22 months from the start of imatinib. Eleven patients received filgrastim 5 μg/kg 1–3 times weekly, and 2 patients received filgrastim 5 μg/kg daily; doses were titrated to maintain an absolute neutrophil count (ANC) ≥ 109/L.

RESULTS

Seven of 11 patients (64%) who began treatment with an ANC < 1.5 × 109/L had responses (i.e., their ANC improved to ≥ 2 × 109/L within 21 days); the other 4 patients experienced slower recovery but were able to continue receiving imatinib uninterrupted. Before filgrastim administration was initiated, patients did not receive imatinib (due to neutropenia‐related treatment interruptions) for an average of 21% of the total time since the start of imatinib. This figure decreased to 6% after the start of filgrastim treatment (P = 0.0008). Before filgrastim treatment was initiated, only one patient had achieved a major (partial) cytogenetic response. After the start of filgrastim treatment, five patients had major cytogenetic responses (including two complete responses).

CONCLUSIONS

The authors concluded that filgrastim may overcome imatinib‐associated neutropenia and allow improved delivery of imatinib. Some patients may experience improvements in their responses to therapy as a result. Cancer 2004. © 2004 American Cancer Society.
DNA‐methylation analysis identifies the E‐cadherin gene as a potential marker of disease progression in patients with monoclonal gammopathies
Authors: Seidl Sonja , Ackermann Jutta , Kaufmann Hannes , Keck Andrea , Nösslinger Thomas , Zielinski Christoph C. , Drach Johannes , Zöchbauer‐Müller Sabine
Published: May 2004

BACKGROUND

Silencing of tumor suppressor genes (TSG) by aberrant methylation (referred to as methylation) contributes to the pathogenesis of various human malignancies. However, little is known about the methylation of known and putative TSGs in monoclonal gammopathies. Thus, the authors investigated the methylation frequencies of 10 genes in patients with monoclonal gammopathies.

METHODS

The methylation patterns of the genes p16INK4a (p16), tissue inhibitor of metalloproteinase 3 (TIMP3), p15INK4b (p15), E‐cadherin (ECAD), death‐associated protein kinase (DAPK), p73, RAS‐association domain family 1A (RASSF1A), p14, O6‐methylguanine DNA methyltransferase (MGMT), and retinoid acid receptor β2 (RARβ) were determined in patients with monoclonal gammopathy of undetermined significance (MGUS; n = 29), smoldering multiple myeloma (SMM; n = 5), multiple myeloma (MM; n = 113), or plasma cell leukemia (PCL; n = 7) by methylation‐specific polymerase chain reaction analysis.

RESULTS

Methylation frequencies for p16, TIMP3, p15, ECAD, DAPK, p73, RASSF1A, p14, MGMT, and RARβ were as follows: 28%, 35%, 10%, 0%, 17%, 21%, 14%, 14%, 7%, and 0%, respectively, in patients with MGUS and 36%, 29%, 27%, 27%, 22%, 15%, 15%, 9%, 4%, and 0%, respectively, in patients with MM. Methylation of at least 1 of these genes was detected in 79% of patients with MGUS and in 80% of patients with MM. Although methylation of ECAD was not detected in patients with MGUS, it was observed frequently in patients with MM and with even greater frequency in patients with PCL. It is noteworthy that an association was found between ECAD methylation and poor prognostic markers in patients with MM.

CONCLUSIONS

Methylation of certain genes can be detected frequently in patients with monoclonal gammopathies. The current data suggest that methylation of ECAD is a marker of disease progression in patients with MM and PCL. Cancer 2004. © 2004 American Cancer Society.
Pathologic T1 clear cell renal cell carcinoma: Insulin‐like growth factor‐I receptor expression and disease‐specific survival
Authors: Parker Alexander S. , Cheville John C. , Blute Michael L. , Igel Todd , Lohse Christine M. , Cerhan James R.
Published: May 2004

BACKGROUND

A proportion of patients diagnosed with pathologic T1 (pT1) clear cell renal cell carcinoma (CC‐RCC) will experience disease progression and death after surgery, whereas the majority remain disease free. The authors conducted a case–cohort investigation to examine the association of insulin‐like growth factor I receptor (IGF‐IR) expression and disease‐specific survival in patients who underwent surgery for pT1 CC‐RCC.

METHODS

Eligible patients included those diagnosed with solitary, nonfamilial pT1 CC‐RCC who underwent radical nephrectomy at the Mayo Clinic‐Rochester between 1970 and 2000 (n = 886 patients). Among this group, 136 patients died of CC‐RCC (cases). Archived tumor blocks were not available for 62 patients, leaving a final study group of 74 cases. Stratified, random sampling was used to select a cohort of at least 3 year‐matched controls (no CC‐RCC death) for each case (n = 263 patients). Detection of IGF‐IR was performed using a commercially available monoclonal antibody. Cox proportional hazards models were fit to assess the association between IGF‐IR expression and disease‐specific survival.

RESULTS

After adjustment for age, the risk of death from CC‐RCC was greater for patients who had tumors that stained positive for IGF‐IR compared with patients who had tumors that showed no IGF‐IR expression (hazard ratio [HR], 1.5; 95% confidence interval, [95% CI], 0.9–2.4). In a stratified analysis, the risk was stronger among patients who had high‐grade tumors (HR, 2.2; 95% CI, 1.1–4.3) compared with patients who had low‐grade tumors (HR, 0.7; 95% CI, 0.3–1.5). Multivariate adjustment for tumor size and histologic tumor necrosis attenuated the association among all patients (HR, 1.3; 95% CI, 0.8–2.1) but strengthened the association among patients with high‐grade tumors (HR, 2.7; 95% CI, 1.3–5.6).

CONCLUSIONS

The current data suggest that IGF‐IR expression is associated with poor survival in patients who are diagnosed with early‐stage CC‐RCC, especially among those with high‐grade disease. Cancer 2004. © 2004 American Cancer Society.
The cost‐effectiveness of aspirin versus cyclooxygenase‐2‐selective inhibitors for colorectal carcinoma chemoprevention in healthy individuals
Authors: Hur Chin , Simon Lee S. , Gazelle G. Scott
Published: May 2004

BACKGROUND

Aspirin therapy is accepted widely for secondary prevention in patients with documented cardiovascular disease, but there is a growing trend among healthy individuals to use aspirin as primary chemoprevention for both cardiovascular and oncologic diseases. Accruing evidence suggests that cyclooxygenase‐2‐selective inhibitors (coxibs) may be effective for colorectal carcinoma (CRC) chemoprevention but would not provide the primary cardiac benefit of aspirin.

METHODS

A computer‐based Markov model simulated hypothetical cohorts of healthy men age 50 years who took either 325 mg of enteric‐coated aspirin daily or celecoxib at a dose of 400 mg twice a day. Patients in both cohorts could develop drug‐related complications that would lead to its discontinuation. The aspirin group also was modeled to have a decreased rate of coronary ischemic events; however, decreased CRC mortality was not modeled in either group based on the assumption that the two treatments were effective equally in this regard. Data sources included published literature and the Centers for Medicare and Medicaid Services. Endpoints used to compare the two strategies included quality‐adjusted life years (QALYs), mortality and complication rates, and cost. The analysis was from a societal perspective with a time horizon of 10 years from age 50 years. Extensive sensitivity analyses were performed.

RESULTS

Aspirin therapy resulted in 0.03 more QALYs and cost $23,000 less than coxib therapy over a 10‐year period. Compared with the aspirin group, the coxib group had 3.877% more complications and 0.17% more deaths. Alternatively stated, coxib therapy resulted in 1 patient complication or death for every 26 or 588 patients treated with coxibs, respectively.

CONCLUSIONS

Assuming equal efficacy in CRC prevention over a 10‐year period, aspirin was both more effective and less costly than coxib therapy when used for primary chemoprevention of CRC. Cancer 2004; © 2004 American Cancer Society.
HIV infection of primary human T cells is determined by tunable thresholds of T cell activation
Authors: Oswald‐Richter Kyra , Grill Stacy M. , Leelawong Mindy , Unutmaz Derya
Published: May 2004

HIV infection of primary human T cells requires T cell activation signals. However, how strength, duration, and quality of TCR signals affect susceptibility of resting human T cells to HIV infection remains poorly understood. We found that the same threshold and duration of antigen signals that lead to optimal T cell activation are required for HIV to progress beyond the level of reversetranscription within resting T cells. Remarkably, sustained cytokine signaling from the IL‐2 receptor following TCR triggering was critical in establishing productive infection. While blockade of TCR signaling pathways with inhibitors of the phosphatidylinositol 3‐kinase pathway caused a partial pre‐integration block, another inhibitor, rapamycin, completely suppressed the infection. In contrast, cyclosporin A or FK506, inhibitors of NFAT, failed to block infection if the T cells were pre‐activated. Collectively, these results bring to light significant parallels between successful HIV infection and optimal thresholds of T cell activation. Furthermore, our results underscore the critical role of IL‐2 signaling in establishing productive HIV infection. These findings have important implications for our understanding of the complex interplay of HIV with host factors induced upon T cell activation.
GSTM1, GSTT1, and GSTP1 genotypes and the genotoxicity of hydroquinone in human lymphocytes
Authors: Silva Maria do Céu , Gaspar Jorge , Duarte Silva Isabel , Faber Ana , Rueff José
Published: May 2004

Hydroquinone is a myelotoxin that is found in many foods and is also formed through the metabolism of benzene. Human exposure to benzene is associated with the development of myelodysplastic syndrome and acute myelogenous leukemia. Hydroquinone is genotoxic in several in vitro and in vivo test systems, inducing micronuclei (MN), sister‐chromatid exchange (SCE), and chromosomal aberrations. Glutathione S‐transferases (GSTs) are a superfamily of polymorphic enzymes involved in the conjugation of reactive chemical intermediates to soluble forms. These enzymes play a key role in the detoxification of endogenous and exogenous compounds, and the polymorphic genes GSTM1, GSTT1, and GSTP1 have been associated with the differential metabolism of several genotoxicants. In the present study, we have evaluated the effect of GSTM1, GSTT1, and GSTP1 polymorphisms on the frequency of MN and SCE induced by hydroquinone in human lymphocytes. Lymphocytes were obtained from 15 healthy non‐smoking donors, and their GSTM1, GSTT1, and GSTP1 genotypes determined. Treatment of cultures of the lymphocytes with hydroquinone significantly increased the overall frequencies of MN and SCE (P<0.0001). Individuals with the GSTM1 null genotype had a significantly higher frequency of MN compared with GSTM1‐present individuals (P=0.013); in contrast, the GSTM1 genotype had no effect on hydroquinone‐induced SCE frequency. The other polymorphisms did not significantly affect the frequencies of MN or SCE. These results suggest that GSTM1 is involved in the metabolic fate of hydroquinone and that polymorphisms in GSTM1 could be related to inter‐individual differences in DNA damage arising from the exposure to this compound. Environ. Mol. Mutagen. 43:258–264, 2004. © 2004 Wiley‐Liss, Inc.
Bacterial and mammalian‐cell genotoxicity of mixtures of chlorohydroxyfuranones, by‐products of water chlorination
Authors: Mäki‐Paakkanen Jorma , Komulainen Hannu , Kronberg Leif
Published: May 2004

The genotoxic responses of mixtures of four chlorohydroxyfuranones (CHFs), 3‐chloro‐4‐(dichloromethyl)‐5‐hydroxy‐2(5H)‐furanone (MX), 3,4‐dichloro‐5‐hydroxy‐2(5H)‐furanone (MCA), 3‐chloro‐ 4‐(chloromethyl)‐5‐hydroxy‐2(5H)‐furanone (CMCF) and 3‐chloro‐4‐methyl‐5‐hydroxy‐2(5H)‐furanone (MCF), were compared with the genotoxicity of the individual compounds. Genotoxicity was evaluated in the Salmonella reversion assay (Ames test), the in vitro Chinese hamster ovary (CHO) cell Hprt mutation assay, and in the CHO chromosome aberration test. When tested individually, the concentrations of the chemicals that were chosen for the mixtures induced no or only a modest increase in the genotoxic effects, and caused little or no cytotoxicity. In the Ames test, the genotoxic responses caused by the mixtures of CHFs did not follow simple additivity. Synergism was observed with strains TA97 and TA98, and antagonism with strain TA100. In the CHO/Hprt mutation assay, the mutagenic response of the mixtures was inconsistent, with near additivity seen with a mixture of CHFs that resulted in 12% cell survival. In contrast, the four CHFs together consistently caused more structural chromosome damage (mainly chromatid‐type breaks and exchanges) compared to the sum of net effects of the four CHFs tested alone. Also, a potentiating effect was consistently seen for the cytotoxicity of the CHF mixtures both in the CHO/Hprt mutation assay and the chromosome aberration test. The present results indicate that the genotoxic effects of CHF mixtures can be greater than additive. Such effects may be worth considering in the cancer risk assessment of chlorinated drinking water. Environ. Mol. Mutagen. 43:217–225, 2004. © 2004 Wiley‐Liss, Inc.
Cytogenetic biomonitoring of Indian women cooking with biofuels: Micronucleus and chromosomal aberration tests in peripheral blood lymphocytes
Authors: Musthapa M. Syed , Lohani Mohtashim , Tiwari Smita , Mathur Neeraj , Prasad Rajendra , Rahman Qamar
Published: May 2004

India currently has the largest number of indoor air pollution–related health problems in the world, with three‐quarters of its households burning wood, cowdung, or crop residues (“traditional” biomass fuels) for cooking, and the remainder using kerosene and relatively clean‐burning liquefied petroleum gas (LPG). Combustion of these fuels produces various pollutants that may cause serious health effects in exposed populations. In this study, the micronucleus (MN) and chromosomal aberration (CA) assays were used to evaluate the relative amounts of DNA damage produced by the use of these cooking fuels. Cytogenetic evaluation of 179 female subjects showed a significant increase in both MN and CA frequency in blood lymphocytes from users of biomass‐fuels in comparison to lymphocytes from LPG users (used as a reference population). The relative MN and CA frequencies for the users of the various fuels decreased in the order cowdung > cowdung/wood ≥ wood > kerosene ≥ LPG. Further, the results indicated an effect of subject age, and the duration of exposure on the MN and CA frequencies in biomass fuel users. Age had no significant effects on the genotoxicity responses in subjects with ≤10 years of exposure to either biomass fuels or LPG, but in subjects using biomass fuels for >10 years, CA and MN frequencies were higher in older individuals (>30 years of age) than younger subjects. Regardless of age, subjects burning biomass fuels had higher MN and CA frequencies than LPG users only when exposures were of at least 5 years duration. These results indicate that burning biomass‐based fuels increases the frequency of cytogenetic alterations in blood lymphocytes of exposed populations, possibly because of exposure to the various noxious gases and toxic substances present in biomass fuels. These cytogenetic markers could be used in the field to assess the genotoxic consequences of burning various cooking fuels and for early detection of genetic abnormalities in people exposed to various pollutants and toxicants. Environ. Mol. Mutagen. 43:243–249, 2004. © 2004 Wiley‐Liss, Inc.
Effect of deletion of SOS‐induced polymerases, pol II, IV, and V, on spontaneous mutagenesis in Escherichia coli mutD5
Authors: Nowosielska Anetta , Janion Celina , Grzesiuk Elzbieta
Published: May 2004

The E. coli dnaQ gene encodes the ϵ subunit of DNA polymerase III (pol III) responsible for the proofreading activity of this polymerase. The mutD5 mutant of dnaQ chronically expresses the SOS response and exhibits a mutator phenotype. In this study we have constructed a set of E. coli AB1157 mutD5 derivatives deleted in genes encoding SOS‐induced DNA polymerases, pol II, pol IV, and pol V, and estimated the frequency and specificity of spontaneous argE3→Arg+ reversion in exponentially growing and stationary‐phase cells of these strains. We found that pol II exerts a profound effect on the specificity of spontaneous mutation in exponentially growing cells. Analysis of growth‐dependent Arg+ revertants in mutD5 polB+ strains revealed that Arg+ revertants were due to tRNA suppressor formation, whereas those in mutD5 ΔpolB strains arose by back mutation at the argE3 ochre site. In stationary‐phase bacteria, Arg+revertants arose mainly by back mutation, regardless of whether they were proficient or deficient in pol II. Our results also indicate that in a mutD5 background, the absence of pol II led to increased frequency of Arg+ growth‐dependent revertants, whereas the lack of pol V caused its dramatic decrease, especially in mutD5 ΔumuDC and mutD5 ΔumuDC ΔpolB strains. In contrast, the rate of stationary‐phase Arg+revertants increased in the absence of pol IV in the mutD5 ΔdinB strain. We postulate that the proofreading activity of pol II excises DNA lesions in exponentially growing cells, whereas pol V and pol IV are more active in stationary‐phase cultures. Environ. Mol. Mutagen. 43:226–234, 2004. © 2004 Wiley‐Liss, Inc.
Hprt mutant frequencies in splenic T‐cells of male F344 rats exposed by inhalation to propylene
Authors: Walker Dale M. , Seilkop Steven K. , Scott Bobby R. , Walker Vernon E.
Published: May 2004

Propylene is a major industrial intermediate and atmospheric pollutant to which humans are exposed by inhalation. In this study, 6‐week‐old male F344 rates were exposed to 0, 200, 2000, or 10,000 ppm propylene by inhalation for 4 weeks (6 h/day, 5 days/week), and mutant frequencies were determined in the Hprt gene of splenic T‐lymphocytes. Twenty milligrams of cyclophosphamide monohydrate (CPP)/kg bw, given on the penultimate day of propylene exposure, was used as a positive control mutagen. Rats (n = 8/group) were necropsied for isolation of T‐cells 8 weeks after the last dose, a sampling time that produced peak spleen Hprt mutant frequencies (Mfs) in a preliminary mutant manifestation study using CCP treatment. Hprt Mfs were measured via the T‐cell cloning assay, which was performed without knowledge of the animal treatment groups. Mean Hprt Mfs were significantly increased over control values (mean Mf = 5.24 ± 1.55 (SD) × 10−6) in CPP‐treated rats (10.37 ± 4.30 × 10−6, P = 0.007). However, Hprt Mfs in propylene‐exposed rats were not significantly increased over background, with mean Mfs of 4.90 ± 1.84 × 10−6 (P = 0.152), 5.05 ± 3.70 × 10−6 (P = 0.895), and 5.95 ± 2.49 ×10−6 (P = 0.500) for animals exposed to 200, 2000, or 10,000 ppm propylene, respectively. No significant increase in F344 rat or B6C3F1 mouse cancer incidence was reported in the National Toxicology Program carcinogenicity studies of propylene across this same exposure range. Taken together, these findings support the conclusion that inhalation exposure of rats to propylene does not cause mutations or cancer. Environ. Mol. Mutagen. 43:265–272, 2004. © 2004 Wiley‐Liss, Inc.
Use of RNA‐arbitrarily‐primed PCR to detect the induction of gene expression in freshwater bivalves (Unio tumidus) transplanted into the Moselle River
Authors: Rodius François , Hammer Claude , Vasseur Paule
Published: May 2004

RNA‐arbitrarily‐primed PCR (RAP‐PCR) can be used to detect changes in gene expression in organisms for which only minimal genomic information is available. In this study, RAP‐PCR was used to detect modification of mRNA expression in the freshwater bivalve Unio tumidus, a mussel commonly used as a sentinel species in field studies. RNA expression was analyzed in the digestive glands of mussels from a control pond and in mussels transplanted into two sites on the Moselle River. The analysis identified a product in all animals exposed to sediments at the river station located downstream of a heavily populated area. This product was not present in animals exposed at the upstream station or at the control site. The additional PCR product was cloned and sequenced, and specific oligonucleotides for the sequence were designed to amplify cDNAs from control and transplanted mussels. A signal was obtained only with the cDNAs from animals exposed at the downstream station, confirming that the variation detected by RAP‐PCR corresponds to an increase of gene expression. Chemical analysis of sediments from the control and river sites indicated that the levels of several potential pollutants were similar at the three locations and below currently accepted pollution thresholds. Our results indicate that RAP‐PCR is a sensitive technique that can be applied in field studies to identify modifications in the gene expression of bioindicator species. This approach can complement chemical, biochemical and population studies to assess the impact of human activity on the ecological quality of aquatic systems. Environ. Mol. Mutagen. 43:209–216, 2004. © 2004 Wiley‐Liss, Inc.
DNA damage in peripheral blood lymphocytes of individuals residing near a wastewater drain and using underground water resources
Authors: Gandhi Gursatej , Kumar Naresh
Published: May 2004

Mahal is a linear village settlement situated about 0.5 km from an open waste‐water drain, the Tung Dhab drain, which carries effluents from local industrial sites. Villagers generally have a low‐to‐middle socio‐economic status and use ground water or a combination of ground water and tap water for drinking and for their other daily activities. The land in and around Mahal is used for agriculture and is irrigated by water from the Tung Dhab. The drain water contains heavy metals, and there is a possibility that these and other contaminants may reach the ground water table of Mahal and thereby compromise the health of the residents. The comet assay was performed on peripheral blood lymphocytes from Mahal villagers and revealed statistically significant increases in DNA damage as compared to a control group that does not use ground water. DNA damage was also significantly related to the age of the villagers and to the length of residence in the village. In the absence of other environmental exposures, it is concluded that the elevated DNA damage in the villagers is a consequence of continuous utilization of contaminated ground water. Environ. Mol. Mutagen. 43:235–242, 2004. © 2004 Wiley‐Liss, Inc.
Activity of topoisomerase inhibitors daunorubicin, idarubicin, and aclarubicin in the Drosophila Somatic Mutation and Recombination Test
Authors: Lehmann Mauricio , Vilar Knulp de Souza Prudente , Franco Aline , Reguly Maria Luíza , de Andrade Heloísa Helena Rodrigues
Published: May 2004

Anthracyclines have been widely used as anticancer drugs against different types of human cancers. The present study evaluated the mutagenic and recombinagenic properties of two anthracycline topoisomerase II (topo II) poisons, daunorubicin (DNR) and idarubicin (IDA), as well as the related topo II catalytic inhibitor aclarubicin (ACLA), using the wing Somatic Mutation and Recombination Test (SMART) in Drosophila melanogaster. The three anthracyclines were positive in this bioassay, producing mainly mitotic homologous recombination. The results for spot‐size distribution and recombinagenic activity indicate that recombinational DNA damage accounts for ∼91, 86, and 62% of DNR, IDA, and ACLA genotoxicity, respectively. Besides being a catalytic inhibitor of topo II, ACLA is also a topoisomerase I (topo I) poison. This dual topo I and II inhibitory effect, associated with its DNA‐intercalating activity, could contribute to the activity of ACLA in the SMART assay. Environ. Mol. Mutagen. 43:250–257, 2004. © 2004 Wiley‐Liss, Inc.
Beitrag zum Vorkommen der Chromgelben Kratertrüffel – Pachyphloeus citrinusBerk. & Br. (Ascomycetes)
Authors: Hensel G. , Huth M.
Published: May 2004

Es wird über das Vorkommen von Pachyphloeus citrinus in Deutschland und Europa berichtet. Ökologie und Phänologie werden diskutiert. Als Basis für eine weitere Bearbeitung werden die deutschen Funde zusammengestellt. (© 2004 WILEY‐VCH Verlag GmbH & Co. KGaA, Weinheim)
Vier neue Arten aus den Gattungen Leucoagaricus und Leucocoprinus mit bräunlichen bis rußfarbigen Tönungen in den Hutfarben
Authors: Mohr P. , Ludwig E.
Published: May 2004

Vier neue Arten aus den Gattungen Leucoagaricus und Leucocoprinus werden beschrieben und gegen bekannte ähnliche Arten abgegrenzt. Leucoagaricus fuligineodiscus P.Mohr & E.Ludwig sp. nova stammt aus Brandenburg im östlichen Teil Deutschlands. Die anderen drei Arten, Leucoagaricus atroalbus P.Mohr & R.M.Dähncke sp. nova, L. brunneosquamulosus P.Mohr & R.M.Dähncke sp. nova und Leucocoprinus canariensis P.Mohr & R.M.Dähncke sp. nova, wurden auf La Palma, Kanarische Inseln (Spanien) gefunden. Leucocoprinus mauritianus (Henn.) P.Mohr wird neu kombiniert, Leucocoprinus heinemannii Migliozzi var. melanotrichoides P.Mohr neu aufgestellt. (© 2004 WILEY‐VCH Verlag GmbH & Co. KGaA, Weinheim)