bluuebunny/crossref_metadata_2025 huggingface dataset:
A comparison of the effects of dorzolamide/timolol fixed combination versus latanoprost on intraocular pressure and pulsatile ocular blood flow in primary open‐angle glaucoma patients
Authors: Janulevicienë I. , Harris A. , Kagemann L. , Siesky B. , McCranor L.
Published: December 2004

Purpose:  To evaluate the effects of dorzolamide/timolol fixed combination (D/T) compared to latanoprost on intraocular pressure (IOP) and pulsatile ocular blood flow (POBF) in primary open‐angle glaucoma (POAG) patients.

Methods:  Thirty patients with POAG were randomized in an open‐label, cross‐over study. Intraocular pressure reduction was achieved by 4 weeks medical therapy with D/T twice daily or latanoprost 0.005% dosed once in the evening. During a 4‐week run–in and a 4‐week wash‐out period between study arms, patients ceased use of all other glaucoma medications and used timolol maleate 0.5% twice daily. Primary efficacy variables were IOP and POBF.

Results:  There was no difference in baseline IOP and POBF parameters between the two study arms. Both D/T and latanoprost statistically significantly reduced IOP by 4.6 mmHg (p < 0.0001) and 3.75 mmHg (p < 0.0001) and increased POBF by 2.048 µl/second (p = 0.0030) and 2.147 µl/second (p = 0.0009), respectively. Repeated measures anova detected significant changes in POBF with treatment (p = 0.0361). Dorzolamide/timolol fixed combination statistically significantly increased pulse volume by 0.767 µl (p = 0.0087), while latanoprost therapy had no significant effect (p = 0.2407).

Conclusions:  Both drugs had similar effects in terms of IOP reduction. Dorzolamide/timolol significantly increased pulse volume while latanoprost had no effect. Further studies are necessary to establish whether the enhancement of choroidal blood flow can prevent glaucoma progression.
Quantitative analysis of retinopathy in type 2 diabetes: identification of prognostic parameters for developing visual loss secondary to diabetic maculopathy
Authors: Hove M. N. , Kristensen J. K. , Lauritzen T. , Bek T.
Published: December 2004

Purpose:  To describe whether quantitative assessment of early changes in the morphology of retinopathy lesions can predict development of vision‐threatening diabetic maculopathy.

Methods:  We used a nested case‐control study, and we studied 11 type 2 diabetes patients who had developed visual loss secondary to diabetic maculopathy. For each diabetes patient, we also studied three matched control patients who had been followed for a comparable period of time without developing visual loss. Fundus photographs describing the early development of retinopathy were digitized and subjected to a full manual quantitative grading on a computer monitor. Differences in the early development of retinal morphology were compared between the two groups. The outcome parameters were changes in the number and area of haemorrhages and exudates in different regions of the fundus, and the weighted distance of these lesions from the fovea and the optic disc.

Results:  In patients who developed visual loss secondary to diabetic maculopathy there was significant early progression in the total area and number of haemorrhages and exudates. The haemorrhages had progressed in all retinal areas except the area around the optic disc and the temporal vascular arcades. The exudates had progressed temporally from the fovea and in the retinal periphery.

Conclusions:  The results suggest that a quantitative description of the regional development of early diabetic retinopathy may help in identifying patients who will later develop vision‐threatening maculopathy.
Effect of voriconazole on a corneal abscess caused by fusarium
Authors: Polizzi Anna , Siniscalchi Cristina , Mastromarino Antonio , Saccà Sergio C.
Published: December 2004

Purpose:  To describe a case of corneal abscess caused by Fusarium solani that did not respond to common antifungal agents.

Method:  Case report.

Results:  Twenty days after accidental contact with vegetation, a 56‐year‐old man presented with a corneal abscess. Corneal ulceration developed and a perforating keratoplasty was performed. After a microbiological examination, the diagnosis of F. solani infection was made. Systemic and topical amphotericin B and fluconazole were prescribed, with no results. A new abscess formed on the transplanted graft and a wound leak developed. We administered topical and systemic voriconazole. No side‐effects were observed. The choroidal detachment and the surgical transplant recovered completely in 20 days. A vascular leukoma developed at the site of the transplanted corneal abscess.

Conclusion:  From a functional point of view, another corneal transplant will be necessary. Voriconazole was effective in treating a severe keratomycosis caused by F. solani that was resistant to other topical and systemic antifungal agents.
Protective role of corneal epithelium against ultraviolet radiation damage
Authors: Podskochy Alexander
Published: December 2004

Purpose:  It is known that the corneal epithelium strongly absorbs ultraviolet radiation (UVR). The aim of the present study was to examine the protective role of corneal epithelium against UVR damage by comparing the biological effect of UVR exposure on whole corneas with that on de‐epithelialized corneas.

Methods:  Six New Zealand albino rabbit corneas were exposed to UVR centred around 280 nm at a dose that causes biomicroscopically significant keratitis (012 J/cm2). Three corneas underwent manual de‐epithelialization prior to UVR exposure. A control group of three rabbits underwent only manual de‐epithelialization. The animals were killed 76 hours after treatment. The corneas were stained with haematoxylin and evaluated by light microscopy.

Results:  Corneas that underwent only the exposure to UVR showed a loss of epithelial cells in the treated area. No damage to keratocytes or the stroma was detected. Corneas that underwent manual de‐epithelialization showed a loss of epithelial cells, and also keratocytes in the anterior quarter of the corneal stroma. However, corneas that were exposed to UVR after manual de‐epithelialization showed very deep stromal damage. The keratocytes disappeared through the entire thickness of the stroma in the UVR‐exposed area.

Conclusion:  Exposure to UVR at 280 nm alone does not result in any deep damage to the corneal stroma and keratocytes. Manual de‐epithelialization causes the disappearance of anterior keratocytes. However, the stromal damage caused by UVR in the de‐epithelialized corneas was very deep. The corneal epithelium serves to protect the deeper corneal structures against UVR damage, probably by absorbing a substantial amount of the UVR energy applied to the eye.
The effects of coloured light filter overlays on reading rates in age‐related macular degeneration
Authors: Eperjesi Frank , Fowler Colin W. , Evans Bruce J. W.
Published: December 2004

Purpose:  To determine the effect of coloured light filter overlays on reading rates for people with age‐related macular degeneration (AMD).

Method:  Using a prospective clinical trial design, we examined the null hypothesis that coloured light filter overlays do not improve reading rates in AMD when compared to a clear filter. Reading rates for 12 subjects with non‐exudative AMD, associated with a relative scotoma and central fixation (mean age 81 years, SD 5.07 years) were determined using the Rate of Reading Test® (printed, nonsense, lower case sans serif, stationary text) with 10 different, coloured light filter overlays (Intuitive Overlays®; figures in brackets are percentage transmission values); rose (78%), pink (78%), purple (67%), aqua (81%), blue (74%), lime‐green (86%), mint‐green (85%), yellow (93%), orange (83%) and grey (71%). A clear overlay (Roscolene # 00) (360 cdm‐2) with 100% transmittance was used as a control.

Results: 
anova indicated that there was no statistically significant difference in reading rates with the coloured light filter overlays compared to the clear filter. Furthermore, chi‐squared analysis indicated that the rose, purple and blue filters had a significantly poorer overall ranking in terms of reading rates compared to the other coloured and clear light filters.

Conclusion:  Coloured light filter overlays are unlikely to provide a clinically significant improvement in reading rates for people with non‐exudative AMD associated with a relative scotoma and central fixation.
Photodynamic therapy with verteporfin in patients with age‐related macular degeneration and juxtafoveal choroidal neovascularization
Authors: Frennesson Christina I.
Published: December 2004

Purpose:  To investigate the effects of photodynamic therapy (PDT) on juxtafoveal choroidal neovascularization (CNV) in age‐related macular degeneration (AMD) in a clinical patient material.

Methods:  Thirty eyes in 30 consecutive patients with AMD and a juxtafoveal CNV underwent PDT with verteporfin with standard parameters. The patients were followed up for 12 months and retreated every 12 weeks in the event of leakage from CNV. Nineteen patients (63.3%) had a predominantly classic CNV, eight (26.7%) had a 100% occult CNV and three (10%) had a minimally classic lesion. In 27 patients (90%) the lesion was ≤ 3 MPS (Macular Photocoagulation Study) disc diameters and ≤ 3 MPS disc areas.

Results:  There was a positive correlation between duration of symptoms and loss of visual acuity at 12 months (p < 0.02). For predominantly classic lesions, there was a positive correlation between duration of symptoms and lesion size (p < 0.005). At 12 months, leakage had stopped after 3.3 ± 0.9 treatments in 80% of the patients. Visual acuity remained stable in 63.3% of the patients.

Conclusion:  Photodynamic therapy appears to be beneficial in patients with AMD and juxtafoveal CNV.
Corneo‐conjunctival autograft transplantation for pterygium surgery
Authors: Frau Eric , Labétoulle Marc , Lautier‐Frau Marie , Hutchinson Sacha , Offret Hervé
Published: December 2004

Purpose: To evaluate the efficacy of surgical management of pterygium with corneo‐conjunctival autograft transplantation.

Setting: Ophthalmology Department, Bicêtre Hospital, University Paris XI and the Assistance Publique Hôpitaux de Paris, France.

Methods: The records of 104 patients (114 eyes), comprising 40 women and 64 men, who underwent corneo‐conjunctival autograft transplantation for primary (104 eyes) and recurrent (10 eyes) pterygia between 1992 and 1998, were reviewed in a retrospective survey. Follow‐up ranged from 12 to 78 months (mean 22.5 months).

Results: All grafts were planted promptly and donor sites re‐epithelialized with no excessive scar tissue formation. No recurrence was noted. Improvement of visual acuity was achieved in 24 patients and stabilization was achieved in 76 patients. The main complication was progression of corneal astigmatism exceeding 4 dioptres in two patients.

Conclusion: These results indicate that corneo‐conjunctival autograft transplantation is an effective treatment for pterygia.
Management of diabetes using adaptive control
Authors: Hovorka Roman
Published: December 2004

The review focuses on adaptive systems for insulin treatment in type 1 diabetes. The review consists of two parts. First, adaptive approaches are described, which exploit infrequent glucose measurements (four to seven measurements per day). Second, adaptive approaches are described, which exploit frequent or continuous glucose measurements (every hour or more often). Each part is further divided into two subparts separating off‐line and on‐line adaptive techniques. The latter represents treatment strategies, which rely on continuous re‐assessment of the glucoregulatory system. The former refers to treatment strategies, which are fixed for a day or longer and are revisited from time to time. It is concluded that the role of adaptive approaches will increase as new continuous glucose‐sensing monitors reach the market. Copyright © 2004 John Wiley & Sons, Ltd.
Premium 7075 Aluminium Alloys Produced by Reciprocating Extrusion
Authors: Lee S.‐W. , Yeh J.‐W. , Liao Y.‐S.
Published: December 2004

Reciprocating extrusion is a novel method to refine the grains and inclusions of 7075 Al alloy. The reciprocatingly extruded 7075‐T6 alloys exhibit superior strength‐toughness combinations to conventional 7000 series alloys. Their available yield strength used in unstable crack growth condition can reach up to 550 MPa. The improved mechanisms in microstructure and properties are discussed.
Megalourethra: A report of three cases associated with maternal diabetes and a review of the literature—is sonic hedgehog the common pathway?
Authors: Vaux Keith K. , Jones Marilyn C. , Benirschke Kurt , Bird Lynne M. , Jones Kenneth L.
Published: December 2004

The mechanisms by which maternal diabetes causes malformations in the offspring have yet to be elucidated. The purpose of this report is twofold: first, to describe three male infants born with multiple congenital anomalies and megalourethra, a defect which has not been previously reported in infants of women with diabetes; and second, to indicate that the defects seen in association with megalourethra in these three infants are similar to those seen as a consequence of abnormalities in sonic hedgehog, suggesting that maternal diabetes may affect sonic hedgehog expression in susceptible tissues during critical stages of development. Published 2004 Wiley‐Liss, Inc.
Dentin phosphoprotein compound mutation in dentin sialophosphoprotein causes dentinogenesis imperfecta type III
Authors: Dong Juan , Gu TingTing , Jeffords Leticia , MacDougall Mary
Published: December 2004

A rare compound mutation involving a 36 bp deletion and 18 bp insertion within exon 5 of the dentin sialophosphoprotein (DSPP) gene has been identified in a family with dentinogenesis imperfecta type III (DGI‐III). The DSPP gene encodes two major tooth matrix proteins dentin sialoprotein (DSP) and dentin phosphoprotein (DPP). DSPP mutations associated with DGI‐III results in an in frame truncation of the serine aspartic acid triplet repeat found in DPP near the highly conserved carboxyl terminal region shortening the protein by six amino acids. Clinically this family presents with discolored amber opalescent teeth and severe attrition of the tooth structure. This study is the first report of a mutation within DPP associated with a genetic dentin disease. Our study indicates that DGI‐III is allelic with some forms of DGI‐II with and without progressive hearing loss and dentin dysplasia type II that have been shown to be caused by mutations within the DSP coding or signal peptide regions. © 2004 Wiley‐Liss, Inc.
Optothermomechanical device for the interferometric characterization of fibers
Authors: Hamza A. A. , Sokkar T. Z. N. , El‐Farahaty K. A. , El‐Dessouky H. M.
Published: December 2004

An optothermomechanical (OTM) device was designed and constructed for fiber characterization with a double‐beam interference microscope. This device enabled us to correlate both the mechanical properties and the thermal properties with the optical properties of fibers. The OTM device consisted of three parts, which were used for the drawing (stress–strain), cooling, and heating of the fibers. The designed OTM device (cooling and heating) was attached to the Pluta microscope for the determination of the optical properties of high‐density polyethylene (PE) fibers at different temperatures (0–50°C). Also, this OTM device (drawing and heating), connected to the Pluta microscope, was used to study the influence of the temperature (10–50°C) and draw ratio (1–7) simultaneously on the optical properties of polypropylene (PP) fibers. Microinterferograms were provided for illustration. © 2004 Wiley Periodicals, Inc. J Appl Polym Sci 95: 647–658, 2005
Culture of Escherichia coli under dissolved oxygen gradients simulated in a two‐compartment scale‐down system: Metabolic response and production of recombinant protein
Authors: Sandoval‐Basurto Edgar A. , Gosset Guillermo , Bolívar Francisco , Ramírez Octavio T.
Published: December 2004

A significant problem of large‐scale cultures, but scarcely studied for recombinant E. coli, is the presence of gradients in dissolved oxygen tension (DOT). In this study, the effect of DOT gradients on the metabolic response of E. coli and production of recombinant pre‐proinsulin, accumulated as inclusion bodies, was determined. DOT gradients were simulated in a two‐compartment scale‐down system consisting of two interconnected stirred‐tank bioreactors, one maintained at anoxic conditions and the other at a DOT of at least 6%. Cells were continuously circulated between both vessels to simulate circulation times (tc) of 20, 50, 90, and 180 sec. A complete kinetic and stoichiometric characterization was performed in the scale‐down system as well as in control cultures maintained at constant DOT in the range of 0–20%. The performance of E. coli cultured under oscillating DOT was significantly affected, even at a tc of 20 sec corresponding to transient exposures of only 13.3 sec to anaerobic conditions. Specific growth rate decreased linearly with tc to a maximum reduction of 30% at the highest tc tested. The negative effect of DOT gradients was even more pronounced for the overall biomass yield on glucose and the maximum concentration and yield of pre‐proinsulin. In these cases, the losses were 9%, 27%, and 20%, respectively, at tc of 20 sec and 65%, 94%, and 87%, respectively, at tc of 180 sec. Acetic, lactic, formic, and succinic acids accumulated during oscillatory DOT cultures, indicating that deviation of carbon flow to anaerobic metabolism was responsible for the observed losses. The results of this study indicate that even very short exposures to anaerobic conditions, typical of large‐scale operations, can substantially reduce recombinant protein productivity. The information presented here is useful for establishing improved rational scale‐up strategies and understanding the behavior of recombinant E. coli exposed to DOT gradients. © 2004 Wiley Periodicals, Inc.
Five-year follow-up of a randomized clinical trial of laparoscopic total versus anterior 180° fundoplication
Authors: Ludemann R , Watson D I , Jamieson G G , Game P A , Devitt P G
Published: December 2004

Background

Total fundoplication for gastro-oesophageal reflux disease may be followed by unwanted side-effects. A randomized trial demonstrated that an anterior 180° partial fundoplication achieved effective reflux control and was associated with fewer side-effects in the short term than total fundoplication. This paper reports longer-term (5 year) outcomes from that trial.

Methods

Between December 1995 and June 1997, 107 patients were randomized to undergo either laparoscopic total fundoplication or a laparoscopic anterior 180° fundoplication. After 5 years, 101 of 103 eligible patients (51 total, 50 anterior) were available for follow-up. Each patient was interviewed by a single blinded investigator and a standardized questionnaire was completed. The questionnaire focused on symptoms and overall satisfaction with the results of fundoplication.

Results

There were no significant differences between the two groups with regard to control of heartburn or patient satisfaction with the overall outcome. Dysphagia, measured by a visual analogue score for solid food and a composite dysphagia score, was worse at 5 years after total fundoplication. Symptoms of bloating, inability to belch and flatulence were also more common after total fundoplication. Reoperation was required for dysphagia in three patients after total fundoplication and for recurrent reflux in three patients after anterior fundoplication.

Conclusion

Anterior 180° partial fundoplication was as effective as total fundoplication for managing the symptoms of gastro-oesophageal reflux in the longer term. It was associated with a lower incidence of side-effects, although this was offset by a slightly higher risk of recurrent reflux symptoms.
Lower gastrointestinal symptoms are not predictive of colorectal neoplasia in a faecal occult blood screen-positive population
Authors: Ahmed S , Leslie A , Thaha M A , Carey F A , Steele R J C
Published: December 2004

Background

The aim of this study was to evaluate the incidence of lower gastrointestinal symptoms in faecal occult blood (FOB) test-positive participants in a colorectal screening programme, and to compare the colonoscopic findings in symptomatic and asymptomatic individuals.

Methods

Five hundred and sixty-three consecutive individuals with a positive FOB test in the Scottish arm of the national colorectal cancer screening pilot were studied. All were aged between 50 and 69 years and underwent colonoscopy. Before the procedure the participants were given a standard questionnaire to elicit gastrointestinal symptoms; these were correlated with the colonoscopic findings.

Results

Of the 563 participants, 439 (78·0 per cent) had one or more lower gastrointestinal symptoms and 124 (22·0 per cent) were symptom free. Taking adenoma and carcinoma together, 322 (57·2 per cent) of the subjects were found to have colorectal neoplasia, and 128 (22·7 per cent) had a completely normal colon. Rectal bleeding was the most common symptom, followed by change in bowel habit, abdominal pain, tenesmus, unexplained weight loss, rectal pain and unexplained anaemia. No significant associations were found between any of these symptoms and the findings at colonoscopy.

Conclusion

In a FOB test-positive screened population, lower gastrointestinal symptoms are common, but are not predictive of colorectal neoplasia.
High speed sliding of axonemal microtubules produced by outer arm dynein
Authors: Seetharam Raviraja N. , Satir Peter
Published: December 2004

To study dynein arm activity at high temporal resolution, axonemal sliding was measured field by field for wild type and dynein arm mutants of Tetrahymena thermophila. For wt SB255 cells, when the rate of data acquisition was 60 fps, about 5× greater than previously published observations, sliding was observed to be discontinuous with very high velocity sliding (average 196 μm/sec) for a few msec (1 or 2 fields) followed by a pause of several fields. The sliding velocities measured were an order of magnitude greater than rates previously measured by video analysis. However, when the data were analyzed at 12 fps for the same axonemes, consistent with previous observations, sliding was linear as the axonemes extended several times their original length with an average velocity of ≈10 μm/sec. The pauses or stops occurred at approximately 200 and 300% of the initial length, suggesting that dynein arms on one axonemal doublet were initially active to the limit of extension, and then the arms on the next doublet became activated. In contrast, in a mutant where OADs are missing, sliding observed at 60 fps was continuous and slow (5 μm/sec), as opposed to the discontinuous high‐velocity sliding of SB255 and of the mutant at the permissive temperature where OADs are present. High‐velocity step‐wise sliding was also present in axonemes from an inner arm dynein mutant (KO6). These results indicate that the high‐speed discontinuous pattern of sliding is produced by the mechanochemical activity of outer arm dynein. The rate of sliding is consistent with a low duty ratio of the outer arm dynein and with the operation of each arm along a doublet once per beat. Cell Motil. Cytoskeleton 60:96–103, 2005. © 2004 Wiley‐Liss, Inc.
Leading the way? The European Union at the WSSD
Authors: Burchell Jon , Lightfoot Simon
Published: December 2004

The 2002 World Summit on Sustainable Development (WSSD) presented an important test of how far the European Union's (EU's) commitment to sustainable development had evolved. This article applies the conception of the EU as a normative power to the EU's role at Johannesburg. It examines how the EU operationalized the concept of sustainable development before analysing the role the EU played in the outcomes of the WSSD and the factors that facilitated or constrained the potential extension of an EU norm in this field. In doing so, the article questions the depth of the EU's current commitment to sustainable development, suggesting that while it may represent a leader in some fields of environmental policy it remains some way short of a coherent adoption of sustainable development as an EU norm. As a result, the factors constraining the development of a norm prevented the EU offering strong leadership at the WSSD. Copyright © 2004 John Wiley & Sons, Ltd and ERP Environment.
Numerical realization for analysis of real flows by integrating computation and measurement
Authors: Hayase Toshiyuki , Nisugi Keisuke , Shirai Atsushi
Published: December 2004

In this paper, we deal with a numerical realization, which is a numerical analysis methodology to reproduce real flows by integrating numerical simulation and measurement. It is difficult to measure or calculate field information of real three‐dimensional unsteady flows due to the lack of an experimental field measurement method, as well as of a way to specify the exact boundary or initial conditions in computation. Based on the observer theory, numerical realization is achieved by a combination of numerical simulation, experimental measurement, and a feedback loop to the simulation from the output signals of both methods. The present paper focuses on the problem of how an inappropriate model or insufficient grid resolution influences the performance of the numerical realization in comparison with ordinary simulation. For a fundamental flow with the Karman vortex street behind a square cylinder, two‐dimensional analysis is performed by means of numerical realization and ordinary simulation with three grid resolutions. Comparison of the results with those of the experiment proved that the feedback of the experimental measurement significantly reduces the error due to insufficient grid resolution and effectively reduces the error due to inappropriate model assuming two‐dimensionality. Copyright © 2004 John Wiley & Sons, Ltd.
Genetic and epigenetic alteration of the NF2 gene in sporadic meningiomas
Authors: Lomas Jesus , Bello M. Josefa , Arjona Dolores , Alonso M. Eva , Martinez‐Glez Victor , Lopez‐Marin Isabel , Amiñoso Cinthia , de Campos Jose M. , Isla Alberto , Vaquero Jesus , Rey Juan A.
Published: December 2004

The role of the NF2 gene in the development of meningiomas has recently been documented; inactivating mutations plus allelic loss at 22q, the site of this gene (at 22q12), have been identified in both sporadic and neurofibromatosis type 2–associated tumors. Although epigenetic inactivation through aberrant CpG island methylation of the NF2 5′ flanking region has been documented in schwannoma (another NF2‐associated neoplasm), data on participation of this epigenetic modification in meningiomas are not yet widely available. Using methylation‐specific PCR (MSP) plus sequencing, we assessed the presence of aberrant promoter NF2 methylation in a series of 88 meningiomas (61 grade I, 24 grade II, and 3 grade III), in which the allelic constitution at 22q and the NF2 mutational status also were determined by RFLP/microsatellite and PCR‐SSCP analyses. Chromosome 22 allelic loss, NF2 gene mutation, and aberrant NF2 promoter methylation were detected in 49%, 24%, and 26% of cases, respectively. Aberrant NF2 methylation with loss of heterozygosity (LOH) at 22q was found in five cases, and aberrant methylation with NF2 mutation in another; LOH 22q and the mutation were found in 16 samples. The aberrant methylation of the NF2 gene also was the sole alteration in 15 samples, most of which were from grade I tumors. These results indicate that aberrant NF2 hypermethylation may participate in the development of a significant proportion of sporadic meningiomas, primarily those of grade I. ©2005 Wiley‐Liss, Inc.
8p11 myeloproliferative syndrome with a novel t(7;8) translocation leading to fusion of the FGFR1 and TIF1 genes
Authors: Belloni Elena , Trubia Maurizio , Gasparini Patrizia , Micucci Carla , Tapinassi Cinzia , Confalonieri Stefano , Nuciforo Paolo , Martino Bruno , Lo‐Coco Francesco , Pelicci Pier Giuseppe , Di Fiore Pier Paolo
Published: December 2004

8p11 myeloproliferative syndrome (EMS) is a clinical‐pathologic entity characterized by rearrangements involving the FGFR1 gene, which encodes a receptor tyrosine kinase. These rearrangements invariably lead to aberrant fusion proteins in which the kinase activity is constitutively turned on, with resulting oncogenic properties. In this article, we describe a new translocation in EMS, t(7;8)(q34;p11), in which the FGFR1 gene is fused to a previously unidentified partner, the TIF1 gene. We show that both the TIF1–FGFR1 and FGFR1–TIF1 fusion proteins have the potential to be translated as a result of the translocation. Thus, our data extend the involvement of FGFR1 in EMS and lend support to the concept that there is a precise correlation between genotype and phenotype in this disease. © 2004 Wiley‐Liss, Inc.
ATP‐binding cassette superfamily transporter gene expression in human soft tissue sarcomas
Authors: Oda Yoshinao , Saito Tsuyoshi , Tateishi Naomi , Ohishi Yoshihiro , Tamiya Sadafumi , Yamamoto Hidetaka , Yokoyama Ryohei , Uchiumi Takeshi , Iwamoto Yukihide , Kuwano Michihiko , Tsuneyoshi Masazumi
Published: December 2004

The phenomenon of multidrug resistance (MDR) in various malignant neoplasms has been reported as being caused by one or multiple expressions of ATP‐binding cassette (ABC) superfamily protein, including P‐glycoprotein/multidrug resistance (MDR) 1 and the MDR protein (MRP) family. However, their expression levels and distribution within soft tissue sarcomas remain controversial. In 86 cases of surgically resected soft tissue sarcoma, intrinsic mRNA levels of MDR1, MRP1, MRP2 and MRP3 were assessed using a quantitative reverse transcriptase‐PCR (RT‐PCR) method. Moreover, immunohistochemical protein expressions of P‐glycoprotein (P‐gp), MRP1, MRP2, MRP3 and p53 protein were evaluated in concordant paraffin‐embedded material. The mRNA expression and immunohistochemical expression of ABC superfamily transporters were compared to clinicopathologic parameters and proliferative activities as evaluated by the MIB‐1‐labeling index (LI). Among the various histologic types, malignant peripheral nerve sheath tumor (MPNST) showed significantly high levels of MDR1 (p=0.017) and MRP3 (p=0.0384) mRNA expression, compared to the other tumor types. When the immunohistochemical method was compared to the RT‐PCR technique to assess ABC transported expression at the protein and mRNA levels, a significantly close relationship was found between the 2 methods (p<0.05). P‐gp expression was significantly correlated with large tumor size (≥5 cm, p=0.041) and high AJCC stage (stages III and IV) (p=0.0365). Furthermore, cases with nuclear expression of p53 revealed significantly higher levels of MDR1 mRNA expression, compared to those with negative immunoreaction for p53 (p=0.0328). Our results suggest that MDR1/P‐gp expression may have an important role to play in tumor progression in the cases of soft tissue sarcoma, and p53 may be one of the active regulators of the MDR1 transcript. In addition, the high levels of both MDR1 and MRP3 mRNA expression in MPNST may help to explain the poor response of this tumor to anticancer‐drugs.
High‐resolution analysis of 16q22.1 in breast carcinoma using DNA amplifiable probes (multiplex amplifiable probe hybridization technique) and immunohistochemistry
Authors: Rakha Emad A. , Armour John A.L. , Pinder Sarah E. , Paish Claire E. , Ellis Ian O.
Published: December 2004

Loss of the chromosomal material at 16q22.1 is one of the most frequent genetic aberrations found in both lobular and low‐grade nonlobular invasive carcinoma of the breast, indicating the presence of a tumour suppressor gene (TSG) at this region in these tumours. However, the TSG (s) at the 16q22.1 in the more frequent nonlobular carcinomas is still unknown. Multiplex Amplifiable Probe Hybridisation (MAPH) is a simple, accurate and a high‐resolution technique that provides an alternative approach to DNA copy‐number measurement. The aim of our study was to examine the most likely candidate genes at 16q22.1 using MAPH assay combined with protein expression analysis by immunohistochemistry. We identified deletion at 16q22.1 that involves some or all of these genes. We also noticed that the smallest region of deletion at 16q22.1 could be delineated to a 3 Mb region centromeric to the P‐cadherin gene. Apart from the correlation between E‐cadherin protein expression and its gene copy number, no correlation was detected between the expression of E2F‐4, CTCF, TRF2 or P‐cadherin with their gene's copy number. In the malignant tissues, no significant loss or decrease of protein expression of any gene other than E‐cadherin was seen in association with any specific tumour type. No expression of VE‐cadherin or Ksp‐cadherin was detected in the normal and/or malignant tissues of the breast in these cases. However, there was a correlation between increased nuclear expression of E2F‐4 and tumours with higher histological grade (p = 0.04) and positive lymph node disease (p = 0.02), suggesting that it may have an oncogenic rather than a tumour suppressor role. The malignant breast tissues also showed abnormal cytoplasmic cellular localisation of CTCF, compared to its expression in the normal parenchymal cells. In conclusion, we have demonstrated that MAPH is a potential technique for assessment of genomic imbalances in malignant tissues. Although our results support E‐cadherin as the TSG in invasive lobular carcinoma, they argue against the candidacy of E2F‐4, CTCF, TRF2, P‐cadherin, Ksp‐cadherin and VE‐cadherin as TSGs in breast cancer. © 2004 Wiley‐Liss, Inc.
GSK3 and PKB/Akt are associated with integrin‐mediated regulation of PTHrP, IL‐6 and IL‐8 expression in FG pancreatic cancer cells
Authors: Grzesiak John J. , Smith Kathy C. , Burton Douglas W. , Deftos Leonard J. , Bouvet Michael
Published: December 2004

We have demonstrated recently that PTHrP is upregulated in pancreatic adenocarcinoma and that the ECM exerts regulatory control, at least in part, over PTHrP expression. In our present study, we examined the potential signaling interactions between these 2 pathways. Our results demonstrate that, under serum‐free conditions, adhesion of FG pancreatic adenocarcinoma cells on Fn is mediated by the α5β1 integrin, whereas adhesion to Type I collagen is mediated by the α2β1 integrin. α5β1 integrin‐mediated adhesion to Fn results in a phenotype that includes a reduction in cell proliferation, increased E‐cadherin localization in cell–cell contacts, increased β‐catenin localization throughout the cell, inhibition of haptokinetic cell migration, and increased expression of PTHrP, IL‐6 and IL‐8 relative to α2β1 integrin‐mediated adhesion on Type I collagen. A phosphoprotein immunoblotting screen of FG pancreatic cancer cells grown on either Fn or Type I collagen indicates that GSK3 and PKB/Akt are differentially phosphorylated on these 2 substrates. These results implicate GSK3 and PKB/Akt in the integrin‐mediated regulation of PTHrP, IL‐6 and IL‐8 in pancreatic cancer. © 2004 Wiley‐Liss, Inc.
Estimating dose‐response relationship between ethanol and risk of cancer using regression spline models
Authors: Polesel Jerry , Dal Maso Luigino , Bagnardi Vincenzo , Zucchetto Antonella , Zambon Antonella , Levi Fabio , La Vecchia Carlo , Franceschi Silvia
Published: December 2004

Cancers of the upper aero‐digestive tract (i.e., oral cavity, pharynx, larynx and oesophagus) are largely attributable to smoking and drinking habits, but the correct estimation of the dose‐response relationship between alcohol and cancer risk is challenging. Step functions are widely used to estimate risks and to evaluate trends of continuous exposure. However, results are influenced by the selection of the reference category and cutpoints. More flexible models, like spline regression and fractional polynomial models, may be an attractive alternative for avoiding strict assumptions about the dose‐response relationship. Data from a large series of hospital‐based case‐control studies conducted in Italy and the Swiss Canton of Vaud in the last 2 decades were reassessed to compare findings from logistic regression spline models and standard step function analysis. For all examined cancers, the risk increased to the consumption of 150 grams of ethanol per day (1.5 litre/day of wine), with a possible threshold effect emerging for cancer of the pharynx and larynx (<50 grams of ethanol per day) only. For higher consumptions, the risks flattened. Our study suggests that regression spline models can be useful to estimate the pattern of risk of a continuous exposure variable, such as alcohol consumption, and provide more accurate estimates than categorical analysis when ORs within each interval, especially in the reference category, are not homogeneous. © 2004 Wiley‐Liss, Inc.
Treatment of multi‐focal colorectal carcinoma metastatic to the liver of immune‐competent and syngeneic rats by hepatic artery infusion of oncolytic vesicular stomatitis virus
Authors: Shinozaki Katsunori , Ebert Oliver , Woo Savio L.C.
Published: December 2004

Viruses that replicate selectively in cancer cells hold considerable promise as novel therapeutic agents for the treatment of malignancy. We report an orthotopic model of multi‐focal colorectal cancer (CRC) metastases in the livers of syngeneic and immune‐competent rats, which permitted rigorous testing of oncolytic virus vectors as novel therapeutic agents through hepatic arterial infusion for efficacy and safety. Vesicular stomatitis virus (VSV) is a negative‐strand RNA virus with intrinsic oncolytic specificity due to attenuated anti‐viral responses in many tumors. After administration at the maximum tolerated dose, the recombinant VSV vector gained access to multi‐focal hepatic CRC lesions that led to tumor‐selective viral replication and oncolysis. No relevant vector‐associated toxicities were noted and in particular, no damage to the hepatic parenchyma was seen. Moreover, the survival rate of vector‐treated rats was significantly improved over that of animals in the control treatment group (p = 0.015). Our results demonstrate that hepatic arterial administration of oncolytic VSV is both effective and safe in an immune‐competent and syngeneic rat model of multi‐focal CRC liver metastasis, suggesting that it can be developed into an effective therapeutic modality in patients in the future. © 2004 Wiley‐Liss, Inc.
Loss of stearoyl‐CoA desaturase expression is a frequent event in prostate carcinoma
Authors: Moore Stacy , Knudsen Beatrice , True Lawrence D. , Hawley Sarah , Etzioni Ruth , Wade Christian , Gifford David , Coleman Ilsa , Nelson Peter S.
Published: December 2004

Prostate carcinogenesis is influenced by genetic alterations resulting in a biochemical condition that favors cell proliferation and survival. Studies of prostate carcinoma using comparative genomic hybridization and cDNA microarray analysis indicate that numerous biochemical processes may be affected during cellular transformation and progression to an invasive phenotype. Among the consistently observed tumor‐associated changes are alterations in fatty acid metabolism that influence diverse cellular activities such as signaling, energy utilization, and membrane fluidity. Increases in fatty acid synthase (FAS) levels have been shown to be one of the earliest and most frequent molecular alterations in prostate carcinogenesis. We sought to identify tumor‐associated changes in the expression of genes with functional roles associated with lipid metabolism. Defined populations of normal and neoplastic prostate epithelium were acquired by laser capture microdissection and transcript levels were measured by cDNA microarray hybridization. We determined that stearoyl‐CoA desaturase (SCD) transcripts were downregulated in cancer relative to normal epithelium. These results were confirmed by quantitative PCR. Further analysis by immunohistochemical evaluation of radical prostatectomy samples employed a quantitative scoring system with a range of 0–300. The median SCD expression levels were 150, 45 and 10 for normal, PIN and carcinoma samples, respectively. Statistically significant differential SCD expression between normal and cancerous epithelium was determined at the p = 0.001 level, and between PIN and prostate carcinoma at the p = 0.03 level. Of these cases, 92% overexpressed fatty acid synthase (FAS) in cancerous cells and 84.7% exhibited the signature of FAS overexpression and SCD loss in prostate carcinoma as compared to normal prostate epithelium. These results indicate that loss of SCD expression is a frequent event in prostate adenocarcinoma, and further supports a role for altered lipid metabolism as a factor in the process of carcinogenesis. © 2004 Wiley‐Liss, Inc.
Dietary folate intake and k‐ras mutations in sporadic colon and rectal cancer in the Netherlands Cohort Study
Authors: Brink Mirian , Weijenberg Matty P. , de Goeij Anton F.P.M. , Roemen Guido M.J.M. , Lentjes Marjolein H.F.M. , de Bruïne Adriaan P. , van Engeland Manon , Goldbohm R. Alexandra , van den Brandt Piet A.
Published: December 2004

We studied the association between dietary folate and specific K‐ras mutations in colon and rectal cancer in The Netherlands Cohort Study on diet and cancer. After 7.3 years of follow‐up, 448 colon and 160 rectal cancer patients and 3,048 sub‐cohort members (55–69 years at baseline) were available for data analyses. Mutation analysis of the K‐ras gene was carried out on all archival adenocarcinoma specimens. Case–cohort analyses were used to compute adjusted incidence rate ratios (RR) and 95% confidence intervals (CI) for colon and rectal cancer overall and for K‐ras mutation status subgroups according to 100 μg/day increased intake in dietary folate. Dietary folate intake was not significantly associated with colon cancer risk for men or women, neither overall nor with K‐ras mutation status. For rectal cancer, folate intake was associated with a decreased disease risk in men and was most pronounced for K‐ras mutated tumors, whereas an increased association was observed for women. Regarding the K‐ras mutation status in women, an increased association was observed for both wild‐type and mutated K‐ras tumors. Specifically, folate intake was associated with an increased risk of G>T and G>C transversions in rectal tumors (RR = 2.69, 95% CI = 1.43–5.09), but inversely associated with G>A transitions (RR = 0.08, 95% CI = 0.01–0.53). Our data suggest that the effect of folate on rectal cancer risk is different for men and women and depends on the K‐ras mutation status of the tumor. © 2004 Wiley‐Liss, Inc.
Role of cyclooxygenase‐2 in immunomodulation and prognosis of endometrial carcinoma
Authors: Ohno Yumiko , Ohno Satoshi , Suzuki Nobutaka , Kamei Tsutomu , Inagawa Hiroyuki , Soma Gen‐Ichiro , Inoue Masaki
Published: December 2004

Although there are several hypotheses explaining the mechanisms of immune‐privileged status of malignant tumor, the exact pathway has yet to be explored. Cyclooxygenase (COX)‐2 plays a vital role in prognosis of cancer patients in terms of contribution to neoangiogenesis and apoptosis inhibition; however, the impact of COX‐2 in immunomodulation has not been reported. We have evaluated the expression of COX‐2 and its impact on infiltration of immune‐competent cells into the tumor cell nest in endometrial carcinoma. Tissue specimens from 70 endometrial carcinoma patients who had undergone a curative resection were evaluated for COX‐2 expression and host immune status (CD8+ T cells). COX‐2 expression was associated with FIGO stage and myometrial invasion, but there was no statistically significant impact. CD8+ T cells within cancer cell nest (Nest CD8) were inversely correlated with the expression level of COX‐2 (p = 0.0006). Nest CD8 became an independent predictor of patient survival (Hazard ratio = 10.300, p = 0.0304) in Cox's multivariate analysis. The expression level of COX‐2 was found to be a significant predictor of disease relapse in univariate analysis (p = 0.0294) but not in multivariate analysis (p = 0.5949). In conclusion, increased nest CD8 produced a survival advantage in endometrial carcinoma patients. Moreover, tumor‐produced COX‐2, which reduces the infiltration of CD8+ T cells into cancer cell nests, may allow tumors to avoid immune surveillance. © 2004 Wiley‐Liss, Inc.
Cross‐typic specificity and immunotherapeutic potential of a human HPV16 E7‐specific CTL line
Authors: Youde Sarah J. , McCarthy Corinna M. , Thomas Karen J. , Smith Kelly L. , Man Stephen
Published: December 2004

Cervical cancer (CaCx) is strongly associated with human papillomavirus (HPV) infection, particularly HPV types 16 and 18. The constitutive expression of HPV E6 and E7 proteins in CaCx makes them attractive targets for CTL based immunotherapy. However cervical carcinomas may have features, e.g., antigen processing defects, that limit the effectiveness of HPV specific CTL. Furthermore most vaccine development has concentrated on HPV type 16, and it is not clear whether such vaccines could induce CTL able to cross‐react on related oncogenic HPV types, e.g., HPV31 and 52. To investigate these potentially important parameters in vitro, we used a CTL (D4) specific for HPV16 E711–20. D4 was able to kill a variety of HPV16+ CaCx cell lines including those with suspected (CaSki) or known antigen processing defects (C33A), and with low HPV DNA copy number (SiHa). D4 was also able to cross react on a related peptide from HPV52 E7 but not HPV31 E7. Further analysis suggested that D4 cross reactivity against related peptides was influenced both by TCR contact residues and a certain threshold for peptide binding. The HPV cross‐reactivity was confirmed at the whole protein level as D4 was also able to recognize the endogenously processed forms of HPV16 and 52 E7 but not 31 E7. These results suggest that HPV16 E711–20 would be a useful epitope for immunotherapy in both HPV 16 and 52 tumours. Despite this, it is difficult to generate these CTL in response to vaccination, emphasizing the need for definition of novel epitopes and more efficient vaccination strategies. © 2005 Wiley‐Liss, Inc.