bluuebunny/crossref_metadata_2025 huggingface dataset:
Randomized clinical trial of the antiplatelet effects of aspirin–clopidogrel combination versus aspirin alone after lower limb angioplasty
Authors: Cassar K , Ford I , Greaves M , Bachoo P , Brittenden J
Published: December 2004

Background

There is a high risk of reocclusion after successful lower limb angioplasty. Platelets play a central role in this process. The aim of this study was to investigate the antiplatelet effect of a combination of aspirin and clopidogrel compared with aspirin alone in patients with claudication undergoing endovascular revascularization.

Methods

This was a double-blind randomized placebo-controlled trial. Some 132 patients were randomized to clopidogrel and aspirin or placebo and aspirin, with a loading dose 12 h before endovascular intervention. Flow cytometric measurements of platelet fibrinogen binding and P-selectin expression were taken as measures of platelet function at baseline, 12 h after the loading dose, and 1 h, 24 h and 30 days after intervention.

Results

Within 12 h of the loading dose, platelet activation in the clopidogrel group had decreased (P-selectin by 27·3 per cent, P = 0·017; fibrinogen binding by 34·7 per cent, P = 0·024; stimulated fibrinogen binding by 49·2 per cent, P < 0·001). No change was observed in the placebo group. Platelet function in the clopidogrel group was significantly suppressed compared with baseline at 1 h, 24 h and 30 days after endovascular intervention (stimulated fibrinogen binding by 53·9, 51·7 and 57·2 per cent respectively; all P < 0·001).

Conclusion

A combination of clopidogrel and aspirin inhibited platelet function more than aspirin alone in patients with claudication before and after angioplasty.
Impact of a surgical training programme on rectal cancer outcomes in Stockholm
Authors: Martling A , Holm T , Rutqvist L E , Johansson H , Moran B J , Heald R J , Cedermark B
Published: December 2004

Background

Total mesorectal excision (TME) and use of adjuvant radiotherapy are major advances in the treatment of rectal cancer that have emerged in the past 20 years. The aim of this study was to evaluate the effects of an initiative to teach the TME technique on outcomes at 5 years after surgery.

Methods

TME-based surgery was introduced in Stockholm in 1994. The study population comprised all 447 patients who underwent abdominal operations for rectal cancer in Stockholm County during 1995 and 1996. Outcomes were compared with those in the Stockholm I (790 patients) and Stockholm II (542 patients) radiotherapy trials.

Results

The permanent stoma rate was reduced from 60·3 and 55·3 per cent in the Stockholm I and II trials respectively to 26·5 per cent in the TME project (P < 0·001). Five-year local recurrence rates decreased from 21·9 and 19·1 per cent to 8·2 per cent respectively (P < 0·001). Five-year cancer-specific survival rates increased from 66·0 and 65·7 per cent in the Stockholm trials to 77·3 per cent in the TME project (hazard ratio 0·62 (95 per cent confidence interval 0·49 to 0·80); P < 0·001).

Conclusion

A surgical teaching programme had a major impact on rectal cancer outcome.
Randomized clinical trial of laparoscopic versus open appendicectomy for confirmed appendicitis
Authors: Moberg A-C , Berndsen F , Palmquist I , Petersson U , Resch T , Montgomery A
Published: December 2004

Background

Laparoscopy is safe for diagnostic and therapeutic purposes in patients with suspected acute appendicitis. This study compared recovery after laparoscopic (LA) and open appendicectomy (OA) for confirmed appendicitis, carried out by experienced surgeons in an educational setting.

Methods

One hundred and sixty-three patients with laparoscopically confirmed appendicitis suitable for LA were randomized prospectively to either LA or OA in a blinded fashion. The primary endpoint was time to full recovery. Secondary endpoints were operating time, complications, hospital stay and functional status.

Results

There was no significant difference between LA and OA in time to full recovery (9 and 11 days respectively; P = 0·225). Operating time was 55 min in the LA group and 60 min in the OA group (P = 0·416). The complication rate was 8·6 and 11·0 per cent respectively (P = 0·696), and median hospital stay was 2 days in both groups (P = 0·192). Functional status was significantly better in the LA group 7–10 days after operation (P = 0·045).

Conclusion

There was no difference in time to full recovery after LA and OA in patients with laparoscopically confirmed appendicitis. A trend towards better physical activity was noted after the laparoscopic procedure.
Clinical significance of mucin phenotype, β-catenin and matrix metalloproteinase 7 in early undifferentiated gastric carcinoma
Authors: Aihara R , Mochiki E , Nakabayashi T , Akazawa K , Asao T , Kuwano H
Published: December 2004

Background

The aim of this study was to examine the clinical significance of mucin phenotypes of early undifferentiated gastric carcinoma, and to identify variables that might be used to select patients suitable for minimally invasive surgery.

Methods

A total of 129 patients with early undifferentiated gastric carcinoma were studied. The mucin phenotype was determined immunohistochemically using markers for M1, apomucin (MUC) 6 and MUC2. Tumours were classified into gastric (G), intestinal, gastrointestinal (GI) or unclassified type. Undifferentiated carcinomas were classified into signet-ring cell carcinoma (SIG) and non-SIG. The immunoreactivity of matrix metalloproteinase (MMP) 7 and β-catenin was also investigated.

Results

GI-type tumours more commonly expressed non-SIG than SIG histology. The GI phenotype was associated with a higher incidence of submucosal invasion, lymphatic invasion, MMP-7 expression and nuclear accumulation of β-catenin than the G type. Non-SIG histology, and the combination of GI type and nuclear accumulation of β-catenin were independent predictors of submucosal invasion. The combination of GI type and MMP-7 expression independently predicted lymphatic invasion. MMP-7 expression correlated with lymph node metastasis.

Conclusion

GI-type early undifferentiated carcinomas and those with non-SIG histology had increased potential for invasion and metastasis. GI type, MMP-7 expression and nuclear accumulation of β-catenin might prove useful markers in the selection of patients for less invasive surgery.
Inadequate treatment of symptomatic breast cancer
Authors: Kingsmore D B , Hole D J , Gillis C R , George W D
Published: December 2004

Background

Early trials that compared breast and axillary treatments showed differing recurrence rates without significant differences in survival. Consequently, there was a wide range of opinion and practice in the management of breast cancer. The present study explored this variability in surgical management to determine the impact of breast and axillary treatment on recurrence and survival.

Methods

The records of 2776 women with histologically confirmed invasive breast cancer diagnosed between 1986 and 1991 were reviewed. The relationship between adequacy of breast and axillary treatment, recurrence and survival was examined in 2122 women who had surgery with curative intent. A Cox proportional hazards model that included tumour size, node status, grade, socioeconomic status and use of adjuvant therapy was used.

Results

Inadequate treatment was associated with a significantly higher risk of local recurrence after breast-conserving surgery (relative hazard ratio (RHR) 4·19 (95 per cent confidence interval (c.i.) 2·73 to 6·43); P < 0·001). Inadequate axillary treatment was associated with a significantly higher risk of regional recurrence (RHR 2·29 (95 per cent c.i. 1·65 to 3·16); P < 0·001). The risk of death from breast cancer was significantly higher if locoregional treatment was inadequate (RHR 1·29 (95 per cent c.i. 1·07 to 1·55); P = 0·008).

Conclusion

Adequate surgery is fundamental to the optimal treatment of breast cancer. Inadequate surgery resulted in higher recurrence rates despite adjuvant treatments.
Role of biological soil crust cover in bioweathering and protection of sandstones in a semi‐arid landscape (Torrollones de Gabarda, Huesca, Spain)
Authors: Souza‐Egipsy Virginia , Wierzchos Jacek , Sancho Carlos , Belmonte Anchel , Ascaso Carmen
Published: December 2004

Sandstone structural landscapes in the semi‐arid Torrollones de Gabarda area (Province of Huesca, NE Spain) are often covered by a well developed biological soil crust of lichens, mosses and cyanobacteria and black coatings on vertical surfaces. By using scanning electron microscopy with backscattered detector imaging, the biological soil crust studied evidenced high activity in the sandstone–crust interface. Processes such as physical disintegration, etching and dwelling as well as biomineralization by calcium oxalate and ﬁxation of mineral particles by extracellular polymeric substances were observed. On the horizontal sandstone surfaces these processes may cause the occurrence of gnammas and the development of a protective coating that favours intense ﬂaking when the crust is disturbed. On the sandstone cliffs, columnar and tafoni weathering development is clearly guided by the protective action of the biological soil crust. These qualitative observations are important to develop methodologies to address their quantitative importance in geomorphological processes in semi‐arid landscapes. Copyright © 2004 John Wiley & Sons, Ltd.
Short‐term microscale topographic changes of coastal bedrock on shore platforms
Authors: Stephenson Wayne J. , Taylor Anna J. , Hemmingsen Maree A. , Tsujimoto Hidekazu , Kirk Robert M.
Published: December 2004

We report a series of short‐term (diurnal) rock surface monitoring studies on inter‐ and supra‐tidal shore platforms using a traversing micro‐erosion meter at two sites, Kaikoura Peninsula, New Zealand, and Apollo Bay, Victoria, Australia. Statistically signiﬁcant day‐to‐day changes were measured. Surface rise and lowering occurred at rates above instrument error, with a maximum range of 3·378 mm between 1·697 mm (lowering) and ‐1·681 mm (rise). Individual measurements showed rises greater than 2 mm. These daily variations reveal that surface lowering and rise occur at a much shorter time scale than previously reported from other studies. The patterns observed suggest wetting and drying is the most likely process causing surface changes at these temporal scales. We argue that traversing micro‐erosion meter studies operating at a short‐term time scale of day‐to‐day provide meaningful results that open new opportunities for studying rock weathering and erosion in a coastal environment. Copyright © 2004 John Wiley & Sons, Ltd.
Shoreline development, longshore transport and surface wave dynamics, Pleistocene Lake Bonneville, Utah
Authors: Schofield Ian , Jewell Paul , Chan Marjorie , Currey Don , Gregory Matt
Published: December 2004

Point of the Mountain spit and Fingerpoint spit are two of the largest geomorphic features of Pleistocene Lake Bonneville of the western Great Basin, USA. The spits and their associated shorelines show distinctly different geomorphic expression and genesis; this is a function of their positions within the lake and the dynamics of the waves and storms that formed them. Mapping of geomorphic features, geometry of erosional features, and detailed lithologic analysis of shoreline deposits are used to determine dominant modes of sediment erosion and deposition. The Point of the Mountain spit, located in the eastern portion of the basin, was formed as a result of highly fractured bedrock in a salient of the Wasatch Front being exposed to wave trains that approached from the north‐northwest causing north‐to‐south longshore sediment transport. Shoreline development and sediment transport on the southern portion of the spit were minimal. The Fingerpoint spit, located on an island in the northwest portion of the basin, was formed by bidirectional longshore sediment transport as the result of waves that approached from both the north‐northeast and the south‐southwest. Spit development is a function of surface wave energy and direction which in turn is the integrated result of wind direction, wind intensity, and fetch. Wave transport direction determined from ﬁeld measurements at Point of the Mountain spit corresponds very well to the direction of maximum fetch (c. 200 km). For the Fingerpoint spit, the hypothesized wave transport direction from the south corresponds with the direction of maximum fetch (c. 350 km). However, wave energy transport from the north had limited fetch (c. 100 km), implying that wind intensity from the north was relatively large. The geometry of the two large Bonneville spits suggests the predominant wind direction from storms during the Pleistocene was from the north and points the way for future studies that can aid in further understanding the nature of Pleistocene wind ﬁelds in the Great Basin. Copyright © 2004 John Wiley & Sons, Ltd.
Resistance to overland flow due to bed‐load transport on plane mobile beds
Authors: Hu Shixiong , Abrahams Athol D.
Published: December 2004

During bed‐load transport by overland ﬂow, momentum is transferred from the ﬂow to the bed via grain collisions, resulting in a decrease in ﬂow velocity and an increase in ﬂow resistance, herein termed bed‐load transport resistance. In overland ﬂow on mobile plane beds, total ﬂow resistance f consists of grain resistance fg and bed‐load transport resistance fbt. In order to identify and evaluate the relative importance of the factors controlling fbt, 38 ﬂume experiments were performed on slopes of 2·7 and 5·5° using sediment with median diameters of 0·74 and 1·16 mm. All ﬂows were supercritical and turbulent.

This study is an extension of a recent study by Gao and Abrahams (Earth Surface Processes and Landforms 2004, vol. 29, pp. 423–435). These authors found that fbt is controlled by three factors: sediment concentration C, dimensionless sediment diameter D*, and relative submergence h/D, where h is ﬂow depth, D is median sediment diameter. However, a new dimensional analysis identiﬁes two additional factors: Froude number F and slope S. Multiple regression analyses reveal (1) that these ﬁve factors together explain 97 per cent of the variance of fbt, and (2) that S controls fbt entirely through C. The variable C is therefore redundant, and a new functional equation relating fbt to D*, h/D, S and F is developed. This equation may be used to predict fbt. An advantage of this equation is that it may be used to predict fbt without measuring bed‐load transport rate. Copyright © 2004 John Wiley & Sons, Ltd.
Fluid–structure interaction modelling of parachute soft‐landing dynamics
Authors: Stein Keith , Tezduyar Tayfun E. , Sathe Sunil , Benney Richard , Charles Richard
Published: December 2004

Soft landing of a payload with the aid of a retraction device is an important aspect in cargo parachute operations. Accurate simulation of this class of parachute operations with a computer model that takes into account the fluid–structure interactions involved would complement drop tests and support the design of cargo parachute systems. We describe the computational methods developed for this purpose, demonstrate how the computational model works in investigation of different soft‐landing conditions, and show a good correlation between the data from our simulations and drop tests. Copyright © 2004 John Wiley & Sons, Ltd.
Experimental study and mathematical modelling of flashover on extra‐high voltage insulators covered with ice
Authors: Farzaneh‐Dehkordi J. , Zhang J. , Farzaneh M.
Published: December 2004

Using a test method developed at the high‐voltage laboratory of the NSERC/Hydro‐Quebec/UQAC Industrial Chair on Atmospheric Icing of Power Network Equipment (CIGELE), the relation between the minimum flashover voltage VMF and the insulator dry arcing distance for standard porcelain station post insulators, as typically used in Hydro‐Quebec substations, was investigated under icing conditions. The experimental results show that, under wet‐grown ice, known as the most dangerous type of ice for power transmission systems, the VMF increases nonlinearly with an increase in insulator length. Based on these results, an improved mathematical model for predicting the critical flashover voltage versus length of ice‐covered insulators is presented. This model is helpful for understanding the flashover phenomenon on ice‐covered insulators and presents a powerful tool for choosing the proper length of outdoor insulators in cold climate regions. Copyright © 2004 John Wiley & Sons, Ltd.
NAT2 slow acetylator genotype as an important modifier of breast cancer risk
Authors: Sillanpää Pia , Hirvonen Ari , Kataja Vesa , Eskelinen Matti , Kosma Veli‐Matti , Uusitupa Matti , Vainio Harri , Mitrunen Katja
Published: December 2004

N‐acetyltransferase 2 (NAT2) is a polymorphic enzyme participating in the metabolism of numerous pharmaceutical drugs and carcinogens found in tobacco smoke and diet. The NAT2 gene is highly polymorphic and several different allelic variants exist that determine the acetylator phenotype. In the course of our case–control study, we developed a new method based on fluorogenic allele‐specific probes for analyzing the C282T and T341C polymorphisms of the NAT2 gene in 483 Finnish breast cancer patients and 482 healthy population controls. The slow NAT2 acetylation capacity–associated genotypes posed a somewhat increased overall breast cancer risk (odds ratio [OR], 1.32; 95% confidence interval [CI], 1.01–1.73). This association was found to be confined to the advanced (stage III or IV) breast cancer (OR, 2.60; 95% CI, 1.29–5.24). When stratified by smoking habits, women who had smoked <5 pack‐years and carried a NAT2 slow acetylator genotype were at a 2.6‐fold (OR, 2.55; 95% CI, 1.01–6.48) risk of breast cancer. Moreover, women with the NAT2 slow acetylator genotype and low body mass index (BMI) (<25.4 kg/m2) were at somewhat increased risk of this malignancy (OR, 1.60; 95% CI, 1.07–2.39). Our results therefore suggest that NAT2 slow acetylator genotype may be an important modifier of environmentally induced breast cancer risk in Finnish women. © 2004 Wiley‐Liss, Inc.
Antitumor and neurotoxic effects of novel harmine derivatives and structure‐activity relationship analysis
Authors: Chen Qi , Chao Rihui , Chen Hongsheng , Hou Xuerui , Yan Huifang , Zhou Shufeng , Peng Wenlie , Xu Anlong
Published: December 2004

Beta‐carboline alkaloids such as harmine are present in medicinal plants such as Peganum harmala that have been used as folk medicine in anticancer therapy. In our study, 9 harmine derivatives (including harmine) were investigated for their antitumor effects and acute toxicities in mice, and the structure‐activity relationship (SAR) was also analyzed. Administration of these compounds resulted in tumor inhibition rates of 15.3–49.5% in mice bearing Lewis Lung Cancer, sarcoma180 or HepA tumor, with the highest value of 49.5% from compound 6. Acute toxicity studies showed that all these compounds except compounds 2 and 5 caused remarkable acute neurotoxicities manifested by tremble, twitch and jumping. SAR analysis indicated that the formate substitution at R3 of the tricyclic skeleton reduced their neurotoxicity, while the short alkyl or aryl substitution at R9 increased the antitumor activity. The harmine and its derivatives resulted in in vitro cytotoxicity (IC50) values of 0.011–0.021 μmol/ml in HepG2 cells, with compound 8 being the most potent among all agents tested. Compounds 1, 6, 7 and 8 induced apoptosis in HepG2 cells, with the highest apoptotic rate (55.34%) from compound 6. Western blotting analysis demonstrated that compound 6 completely inhibited the expression of Bcl‐2 gene, and compounds 1 and 8 produced a significant inhibition by 40 and 60%, respectively, compared to the control, while compound 7 did not alter the level of Bcl‐2. Compounds 1, 6, 7 and 8 upregulated the expression of death receptor Fas by approximately 50–120%. All these findings indicate that compounds with both substitutions at R3 and R9 (such as compound 5) have high antitumor activity and low toxicity, which might be chosen as lead molecules for further development. Further studies on the effects of harmine derivatives on key regulators for tumor cell apoptosis are needed. © 2004 Wiley‐Liss, Inc.
Use of multiple biomarkers for a molecular diagnosis of prostate cancer
Authors: Landers Kelly A. , Burger Michelle J. , Tebay Michelle A. , Purdie David M. , Scells Betty , Samaratunga Hemamali , Lavin Martin F. , Gardiner Robert A.
Published: December 2004

The identification of biomarkers capable of providing a reliable molecular diagnostic test for prostate cancer (PCa) is highly desirable clinically. We describe here 4 biomarkers, UDP‐N‐Acetyl‐α‐D‐galactosamine transferase (GalNAc‐T3; not previously associated with PCa), PSMA, Hepsin and DD3/PCA3, which, in combination, distinguish prostate cancer from benign prostate hyperplasia (BPH). GalNAc‐T3 was identified as overexpressed in PCa tissues by microarray analysis, confirmed by quantitative real‐time PCR and shown immunohistochemically to be localised to prostate epithelial cells with higher expression in malignant cells. Real‐time quantitative PCR analysis across 21 PCa and 34 BPH tissues showed 4.6‐fold overexpression of GalNAc‐T3 (p = 0.005). The noncoding mRNA (DD3/PCA3) was overexpressed 140‐fold (p = 0.007) in the cancer samples compared to BPH tissues. Hepsin was overexpressed 21‐fold (p = 0.049, whereas the overexpression for PSMA was 66‐fold (p = 0.047). When the gene expression data for these 4 biomarkers was combined in a logistic regression model, a predictive index was obtained that distinguished 100% of the PCa samples from all of the BPH samples. Therefore, combining these genes in a real‐time PCR assay represents a powerful new approach to diagnosing PCa by molecular profiling. (Supplemental material for this article can be found on the International Journal of Cancer website at http://www.interscience.wiley.com/jpages/0020‐7136/suppmat/index.html.) © 2004 Wiley‐Liss, Inc.
Transmigration of human ovarian adenocarcinoma cells through endothelial extracellular matrix involves αv integrins and the participation of MMP2
Authors: Leroy‐Dudal Johanne , Demeilliers Christine , Gallet Olivier , Pauthe Emmanuel , Dutoit Soizic , Agniel Rémy , Gauduchon Pascal , Carreiras Franck
Published: December 2004

The growth of ovarian carcinoma is dependent upon their vascularistion, but the interaction of ovarian cancer cells with the endothelium and their invasion through an endothelial environment remain poorly understood at the molecular level. To investigate adhesive events underlying this process with focusing on the role of αv integrins and MT1MMP‐MMP2 proteinases, we used in vitro models of cocultures of human ovarian adenocarcinoma cell lines (IGROV1 and SKOV3) with human umbilical vein endothelial cells (HUVECs). Immunostaining of HUVECs revealed the network organisation of fibrillar fibronectin (Fn) and pericellular vitronectin (Vn). During coculture, IGROV1 and SKOV3 cells gain access to subendothelial basement membrane of HUVECs and dislocated endothelial Fn without affecting endothelial Vn. Transmigration assays revealed that tumour cells invade Vn and, with an higher efficiency, Fn. Our data also highlighted that ovarian carcinoma cells migrated through the Fn‐rich HUVEC‐ECM. The expression of MMP2 and MT1‐MMP was revealed in tumour cells within an endothelial environment. Furthermore, we found that cell migration through the endothelial ECM was almost totally dependent on αv integrin function, whereas β1 integrins were not solicited. In addition, inhibitors of MMP2 activity (alone or combined with anti‐αv integrin MAb) or TSRI265 (which blocks MMP2‐αvβ3 association) were found to impede this process. Finally, αv integrins, MT1‐MMP and MMP2 were found in ovarian carcinoma cells within the 3‐dimensional architecture of intraperitoneal tumour nodes collected from nude mice xenografted with IGROV1 or SKOV3 cell lines or within human tumour tissues. αv integrins therefore appear as essential to the migration properties of human ovarian carcinoma cells, especially in an endothelial environment, with MMP2 participating to this process. © 2004 Wiley‐Liss, Inc.
Lifetime physical activity and prostate cancer risk
Authors: Pierotti Barbara , Altieri Andrea , Talamini Renato , Montella Maurizio , Tavani Alessandra , Negri Eva , Franceschi Silvia , Vecchia Carlo La
Published: December 2004

The purpose of our study was to investigate the relation in between physical activity in different periods of life at work and in leisure‐time and prostate cancer risk. We conducted a case‐control study on prostate cancer in Italy between 1991 and 2002, which included 1,294 incident cases of histologically confirmed prostate cancer below 75 years of age and 1,451 controls, who were admitted to hospital for acute nonneoplastic conditions. Odds ratios (OR) of prostate cancer according to physical activity in different periods of life were obtained by unconditional multiple logistic regression models, including terms for age, study centre, education, social class, body mass index, energy intake, family history and other selected covariates. Compared to the lowest level of occupational physical activity, the multivariate ORs for prostate cancer for the highest level were 0.94 (95% confidence interval, CI, 0.75–1.17) at age 15–19, 0.78 (95% CI, 0.63–0.97) at age 30–39 and 0.75 (95% CI, 0.61–0.93) at age 50–59. A significant inverse trend in risk was found for activity at work at ages 30–39 and 50–59. The inverse associations were consistent in strata of age at diagnosis, body mass index, education and social class. No significant association was found for leisure‐time physical activity. The inverse association between occupational physical activity and prostate cancer risk may reflect favorable hormonal correlates of physical activity, but residual confounding by socioeconomic covariates cannot be excluded. © 2004 Wiley‐Liss, Inc.
Altered expression and deletion of RMO1 in osteosarcoma
Authors: Eppert Kolja , Wunder Jay S. , Aneliunas Vicky , Tsui Lap‐Chee , Scherer Stephen W. , Andrulis Irene L.
Published: December 2004

In order to increase our understanding of the molecular events underlying osteosarcoma progression, the expression of approximately 950 genes was examined in 24 primary and metastatic osteosarcoma tumor specimens. A gene, RMO1, was isolated with decreased expression in metastatic samples. Real‐Time PCR corroborated this pattern, revealing lower expression in the primary sample in 6 of 7 cases for which both primary and metastatic osteosarcoma samples were available from the same patient (p = 0.034). RMO1 is located at 2q33, a region of frequent loss of heterozygosity in cancer, and exhibited loss of heterozygosity in 6 out of 9 primary osteosarcoma tumor samples (67%). Loss of heterozygosity is evident in primary tumors while the decrease in gene expression is seen in the metastatic samples, indicating that these 2 events are separately implicated in cancer progression. Cloning of RMO1 revealed an open reading frame with multiple splice forms with significant homology to GRB7, 10 and 14 and MIG10 in the region containing a Pleckstrin homology domain and a Ras association domain, suggestive of a role in cell signaling and migration. Northern blot analysis indicated that RMO1 mRNA is ubiquitously expressed in tissues except for peripheral blood leukocytes. These data suggest that RMO1 may be a candidate for a protein involved in inhibiting tumor progression. © 2004 Wiley‐Liss, Inc.
Gene expression profiling identifies IL‐13 receptor α2 chain as a therapeutic target in prostate tumor cells overexpressing adrenomedullin
Authors: Gonzalez‐Moreno Oscar , Calvo Alfonso , Joshi Bharat H. , Abasolo Ibane , Leland Pamela , Wang Zhou , Montuenga Luis , Puri Raj K. , Green Jeffrey E.
Published: December 2004

Human adrenomedullin (AM) is a 52 amino acid peptide, which shares homology with the calcitonin gene‐related peptide. Overexpression of AM in the prostate carcinoma cell line PC‐3 results in growth inhibition with a 20% (for human AM) and 35% (for rat AM) increase in doubling time compared to parental or mock‐transfected cells. We demonstrate by gene expression profiling that AM overexpression results in the dysregulation of approximately 100 genes. Examples of such genes include many involved in the formation of the cytoskeleton, cell adhesion and the extracellular matrix, as well as regulators of the cell cycle and apoptosis, cytokines and transcription factors. Several genes related to cell growth arrest, such as GADD45, IGF‐BP6 and RUNX‐3, are upregulated by AM. Interestingly, interleukin‐13 receptor α2 (IL‐13Rα2) transcripts were significantly increased in clones overexpressing AM, which was confirmed by semiquantitative RT‐PCR analysis. In addition, PC‐3 cells treated with AM showed an overexpression of IL‐13Rα2, which was abolished when cells were preincubated with an anti‐AM blocking antibody. When PC‐3 cells overexpressing AM and the IL‐13Rα2 were treated with the highly specific IL13‐PE38 cytotoxin, which binds to this receptor, a concentration‐dependent inhibition of protein synthesis was observed. The IC50 (concentration of cytotoxin inhibiting protein synthesis by 50%) ranged from 1 to 4 ng/ml. This cytotoxicity was specific as it was neutralized by the excess of IL‐13 and confirmed by clonogenic assays. This study describes a novel AM‐induced mechanism of tumor sensitization through the upregulation of functional IL‐13Rα2 chain, an ideal target for the highly specific recombinant chimeric cytotoxin IL13‐PE38. © 2004 Wiley‐Liss, Inc.
Antimicrobial protein hCAP18/LL‐37 is highly expressed in breast cancer and is a putative growth factor for epithelial cells
Authors: Heilborn Johan D. , Nilsson Margareta Frohm , Jimenez Clara I. Chamorro , Sandstedt Bengt , Borregaard Niels , Tham Emma , Sørensen Ole E. , Weber Günther , Ståhle Mona
Published: December 2004

Human cathelicidin antimicrobial protein hCAP18/LL‐37 is an effector molecule of the nonspecific innate immune system. hCAP18/LL‐37 is present in leukocytes and is expressed in skin and other epithelia, where it is upregulated in association with inflammation and injury. In addition, antimicrobial proteins including cathelicidins have been proposed to play a role in the nonspecific defense against tumors. To assess its potential role in tumor host defense, we investigated the expression of hCAP18/LL‐37 in a series of breast carcinomas. Unexpectedly, we found that hCAP18/LL‐37 was strongly expressed in the tumor cells and not in the adjacent stroma. To test the hypothesis that hCAP18/LL‐37 may provide a growth advantage for the tumor cells, we treated human epithelial cell lines with synthetic biologically active LL‐37 peptide and found a significant increase in cell proliferation. In addition, transgenic expression of hCAP18 in 2 different human epithelial cell lines resulted in increased proliferation of both cell types. These findings do not support the hypothesis that LL‐37 has an antitumor effect, but rather suggest that hCAP18/LL‐37 may promote tumor cell growth in breast cancer. © 2004 Wiley‐Liss, Inc.
Dietary carbohydrates and breast cancer risk: A prospective study of the roles of overall glycemic index and glycemic load
Authors: Silvera Stephanie A. Navarro , Jain Meera , Howe Geoffrey R. , Miller Anthony B. , Rohan Thomas E.
Published: December 2004

We examined breast cancer risk in association with overall glycemic index (GI), glycemic load (GL), and dietary carbohydrate and sugar intake in a prospective cohort of 49,613 Canadian women enrolled in the National Breast Screening Study who completed a self‐administered food frequency questionnaire between 1980 and 1985. Linkages to national mortality and cancer databases yielded data on deaths and cancer incidence, with follow‐up ending between 1998 and 2000. During a mean follow‐up of 16.6 years, we observed 1,461 incident breast cancer cases. GI, GL, total carbohydrate and total sugar intake were not associated with breast cancer risk in the total cohort. However, there was evidence of effect modification of the association between GI and breast cancer risk by menopausal status (p = 0.01), the hazard ratio for the highest versus the lowest quintile level of GI being 0.78 (95% CI = 0.52–1.16; ptrend = 0.12) in premenopausal women and 1.87 (95% CI = 1.18–2.97; ptrend = 0.01) in postmenopausal women. The associations between GI and GL were not modified by body mass index (BMI) or by vigorous physical activity among pre‐ or postmenopausal women. Similarly, the associations between GI/GL and risk in postmenopausal women were not modified by BMI, vigorous physical activity, or ever use of hormone replacement therapy (HRT), although the associations were slightly stronger among those who reported no vigorous physical activity (ptrend = 0.02), among those who reported ever using HRT (ptrend = 0.02) and among normal‐weight women (BMI < 25 kg/m2; ptrend = 0.03). Our data suggest that consumption of diets with high GI values may be associated with increased risk of breast cancer among postmenopausal women, possibly more so among subgroups defined by participation in vigorous physical activity, ever use of HRT and those who are not overweight. © 2005 Wiley‐Liss, Inc.
5‐Aza‐2′‐deoxycytidine induces p21WAF expression by demethylation of p73 leading to p53‐independent apoptosis in myeloid leukemia
Authors: Schmelz Karin , Wagner Mandy , Dörken Bernd , Tamm Ingo
Published: December 2004

The DNA methylation inhibitor 5‐Aza‐2′‐deoxycytidine (5‐Aza‐CdR) has significant therapeutic value for the treatment of patients with myelodysplastic syndrome (MDS), acute myeloid leukemia (AML) and chronic myeloid leukemia (CML). The demethylating effect of 5‐Aza‐CdR has been well characterized. In contrast, less is known about the molecular events downstream of the methylation inhibition. Here, 5‐Aza‐CdR induced apoptosis in AML cells (both p53 mutant and wild‐type) but not in epithelial or normal PBMCs. Cell death was accompanied by activation of the mitochondrial apoptosis pathway, as shown by release of cytochrome c and AIF and loss of mitochondrial membrane potential (ΔΨm). Activation of caspase‐3 (but not −6 and −8) was detectable using Western blot analysis and measurement of caspase enzymatic activity. 5‐Aza‐CdR treatment resulted in the induction of p21, which correlated with the arrest of AML cells in the G1 cell cycle phase. Induction of p21 expression was independent of its promoter methylation status but mediated by 5‐Aza‐CdR‐induced reexpression of the tumor‐suppressor p73, a known upstream regulator of p21. The p73 promoter was hypermethylated in AML cell lines and in primary AML cells but not in epithelial cells, which were resistant toward 5‐Aza‐CdR. Therefore, 5‐Aza‐CdR‐mediated specific killing of myeloid cells might be dependent on its ability to revert p73 promoter methylation and to reexpress p73 mRNA. In addition, exogenous expression of p73 rendered epithelial cells sensitive to apoptosis induced by 5‐Aza‐CdR or other cytostatic drugs. We therefore conclude that p73 is a relevant target for methylation‐dependent efficacy of 5‐Aza‐CdR in AML cells. © 2004 Wiley‐Liss, Inc.
Identification and validation of novel ERBB2 (HER2, NEU) targets including genes involved in angiogenesis
Authors: Beckers Johannes , Herrmann Felix , Rieger Sandra , Drobyshev Alexei L. , Horsch Marion , Hrabé de Angelis Martin , Seliger Barbara
Published: December 2004

V‐erb‐b2 erythroblastic leukemia viral oncogene homolog 2 (ERBB2; synonyms HER2, NEU) encodes a transmembrane glycoprotein with tyrosine kinase‐specific activity that acts as a major switch in different signal‐transduction processes. ERBB2 amplification and overexpression have been found in a number of human cancers, including breast, ovary and kidney carcinoma. Our aim was to detect ERBB2‐regulated target genes that contribute to its tumorigenic effect on a genomewide scale. The differential gene expression profile of ERBB2‐transfected and wild‐type mouse fibroblasts was monitored employing DNA microarrays. Regulated expression of selected genes was verified by RT‐PCR and validated by Western blot analysis. Genomewide gene expression profiling identified (i) known targets of ERBB2 signaling, (ii) genes implicated in tumorigenesis but so far not associated with ERBB2 signaling as well as (iii) genes not yet associated with oncogenic transformation, including novel genes without functional annotation. We also found that at least a fraction of coexpressed genes are closely linked on the genome. ERBB2 overexpression suppresses the transcription of antiangiogenic factors (e.g., Sparc, Timp3, Serpinf1) but induces expression of angiogenic factors (e.g., Klf5, Tnfaip2, Sema3c). Profiling of ERBB2‐dependent gene regulation revealed a compendium of potential diagnostic markers and putative therapeutic targets. Identification of coexpressed genes that colocalize in the genome may indicate gene regulatory mechanisms that require further study to evaluate functional coregulation. (Supplementary material for this article can be found on the International Journal of Cancer website at http://www.interscience.wiley.com/jpages/0020‐7136/suppmat/index.html.) © 2004 Wiley‐Liss, Inc.
Protein from intestinal Eimeria protozoan stimulates IL‐12 release from dendritic cells, exhibits antitumor properties in vivo and is correlated with low intestinal tumorigenicity
Authors: Rosenberg Barnett , Juckett David A. , Aylsworth Charles F. , Dimitrov Nikolay V. , Ho Siu‐Cheong , Judge John W. , Kessel Sarah , Quensen Janet , Wong Kwai‐Pheng Ho , Zlatkin Igor , Zlatkin Tanya
Published: December 2004

The small intestine (SI) of vertebrates exhibits low tumorigenesis and rarely supports metastatic growth from distant tumors. Many theories have been proposed to address this phenomenon, but none has been consistently supported. One candidate mechanism is that the vast immunologic compartment of the SI provides a heightened level of tumor immunosurveillance. Consistent with this, we have identified a molecule of low abundance from bovine SI that has the hallmarks of a potent immunostimulant and may be associated with the natural suppression of cancer in the intestinal tract. The protein originates from an endemic gut protozoan, Eimeria spp., and is homologous to the antigen 3‐1E previously isolated from the avian apicomplexan E. acervulina. We show here that it is a very potent stimulator of IL‐12 release from dendritic cells, upregulates inflammatory modulators in vivo (IL‐12, MCP‐1, IL‐6, TNF‐α and INF‐γ) and has antitumor properties in mice. In addition, it is synergistic in vitro with anti‐CD40 antibody, IFN‐γ, IL‐4 and GM‐CSF; is active across species barriers in vivo; and has no observable toxicity. Based on these activities, we speculate that it is an inducer of protozoan‐targeted innate immunity, which may explain its potential benefit to the intestinal tract and potency as an agent in cancer immunotherapy. © 2004 Wiley‐Liss, Inc.
Growth inhibition of experimental non‐Hodgkin's lymphomas with the targeted cytotoxic somatostatin analogue AN‐238
Authors: Keller Gunhild , Engel Jörg B. , Schally Andrew V. , Nagy Attila , Hammann Brian , Halmos Gabor
Published: December 2004

The cytotoxic analogue of somatostatin, AN‐238, consisting of 2‐pyrrolinodoxorubicin (AN‐201), a superactive derivative of doxorubicin (DOX), linked to somatostatin analogue carrier RC‐121 binds with high affinity to receptors for somatostatin and can be targeted to tumors that express these receptors. Because somatostatin receptors are found in a high percentage of human non‐Hodgkin's lymphomas (NHLs), we evaluated the antitumor effect of AN‐238 in 2 human NHL cell lines in vivo. Nude mice bearing xenografts of RL and HT human NHL were treated with AN‐238 or its components at equimolar doses, and antitumor effects were determined. Expression of mRNA for somatostatin receptor subtypes was measured by RT‐PCR, and the presence of somatostatin receptors was determined by radioligand binding. Toxicity was evaluated by following white blood cell count (WBC) and body weight. AN‐238 significantly (p < 0.05) inhibited growth of RL and HT xenografts and prolonged the tumor doubling time. Cytotoxic radical AN‐201, the unconjugated mixture of somatostatin analogue RC‐121 and AN‐201 or RC‐121 alone had no significant effects. Blockade of somatostatin receptors by excess RC‐121 abolished the effect of AN‐238, demonstrating targeting. Expression of somatostatin receptors was not changed after repeated treatment with AN‐238. AN‐201, but not AN‐238, significantly lowered the WBC and caused a greater decrease in body weight than AN‐238. Our findings demonstrate that targeted chemotherapy with AN‐238 can strongly inhibit the growth of NHL cells, which express somatostatin receptors. AN‐238 could be considered for the treatment for patients with NHL. © 2004 Wiley‐Liss, Inc.
Farnesyltransferase inhibitor SCH‐66336 downregulates secretion of matrix proteinases and inhibits carcinoma cell migration
Authors: Desrosiers Richard R. , Cusson Marie‐Hélène , Turcotte Sandra , Béliveau Richard
Published: December 2004

The ras oncogenes are among those most frequently found in human cancers. Blocking Ras farnesylation is a promising strategy for arresting cancer growth. Ras activates several signaling pathways with key roles in cellular proliferation, invasion, metastasis and angiogenesis. Furthermore, proteolytic activities of matrix proteinases such as urokinase‐type plasminogen activator (uPA) and matrix metalloproteinases (MMPs) are regulated by Ras isoforms. Thus, we investigated the effects of SCH‐66336, a farnesyltransferase inhibitor, on secretion of components of the plasminogen activation system as well as on the gelatinases MMP‐2 and MMP‐9, which play pivotal roles in matrix remodeling. SCH‐66336 up to 5 μM did not significantly alter the viability of prostate (PC‐3) and renal (Caki‐1) cancer cells incubated in serum‐depleted medium. SCH‐66336 partly inhibited the processing of H‐Ras, while levels of mature N‐Ras and K‐Ras remained unaffected. Under these noncytotoxic conditions, uPA and tPA levels were lowered in culture medium but raised in cell lysates, suggesting inhibition of trafficking pathways. In contrast, SCH‐66336 had no effect on uPAR expression or on secreted PAI‐1 levels. As expected, the reduction of uPA and tPA activities by SCH‐66336 inhibited the conversion of plasminogen to plasmin by about 25% in PC‐3 cells. SCH‐66336 also inhibited the levels of secreted pro‐MMP‐2 and pro‐MMP‐9 as well as the release of their inhibitors TIMP‐1 and TIMP‐2. SCH‐66336 decreased both the adhesion and even more so the migration of PC‐3 cells on gelatin. Thus, SCH‐66336 inhibited farnesylation in both cancer cell types, and H‐Ras functions should be reduced by the drug. In addition, the lower levels of secreted proteinases in the presence of SCH‐66336 suggest that reduced matrix remodeling and cell migration should occur in treated tumors. © 2004 Wiley‐Liss, Inc.
A critical comparison of methods for the determination of the aging sensitivity in biomedical grade yttria‐stabilized zirconia
Authors: Deville Sylvain , Gremillard Laurent , Chevalier Jérôme , Fantozzi Gilbert
Published: December 2004

Since the recent failure events of two particular series of zirconia femoral heads for total hip replacement prosthesis, a large decrease in the use of zirconia ceramics for orthopaedic implants has been observed. In spite of the biomedical success of this material during the last 10 years, this decrease in use was required for safety reasons, until the cause of the failures is known. It has been shown that these failures were related to the low temperature hydrothermal degradation (also known as aging). Thus, it is crucial to better understand the aging behavior, in order to be able to assess its importance and then control it if required. In this study, various techniques relevant to assess the hydrothermal degradation sensitivity of biomedical grade yttria‐stabilized zirconia are discussed and compared. The expected outputs of conventional methods, that is, X‐ray diffraction and scanning electron microscopy are examined. More recent methods like optical interferometry and atomic force microscopy are presented, with their respective benefits and drawbacks. An up‐to‐date comparison of these different techniques is provided, and their use for ensuring the long‐term reliability of a particular batch of zirconia in terms of aging degradation is demonstrated. © 2004 Wiley Periodicals, Inc. J Biomed Mater Res Part B: Appl Biomater 72B: 239–245, 2005
Emerging methods for providing clinicians with timely feedback on treatment effectiveness: An introduction
Authors: Lambert Michael J.
Published: December 2004

This article introduces the issue of Journal of Clinical Psychology/In Session devoted to the need for, and value of, providing psychotherapists with feedback about client progress during the course of treatment. After an introduction that sets articles in the series in the context of improving psychotherapy outcome, the seven articles in this special issue are briefly summarized. The articles that follow this introduction provide general principles for effective feedback, highlight therapist difficulties in predicting treatment failure, provide “lab tests” for recognition of poorly responding clients, and demonstrate the powerful effects of providing therapists with feedback on client progress. The articles argue that coupling of statistical modeling techniques with currently available information technology is an innovation to routine clinical practice that clinicians can ill afford to overlook. © 2004 Wiley Periodicals, Inc. J Clin Psychol/In Session.
A lab test and algorithms for identifying clients at risk for treatment failure
Authors: Hannan Corinne , Lambert Michael J. , Harmon Cory , Nielsen Stevan Lars , Smart David W. , Shimokawa Kenichi , Sutton Scott W.
Published: December 2004

Many branches of medicine rely heavily on lab tests to monitor client treatment response and use this information to modify their treatment. By contrast, those who offer psychological interventions seldom rely on formal assessments (lab tests) to monitor their clients' response to treatment. Data are presented that demonstrate that clinicians rarely accurately predict who will not benefit from psychotherapy. This finding is contrasted with the use of a questionnaire (lab test data) and decision rules on the basis of a client's expected progress. Results have indicated that formal methods of monitoring were able to identify 100% of the patients whose condition had deteriorated at termination, and 85% by the time they had attended three treatment sessions. Practitioners are encouraged to consider formal methods of identifying the deteriorating client. © 2004 Wiley Periodicals, Inc. J Clin Psychol/In Session.
The partners for change outcome management system
Authors: Miller Scott D. , Duncan Barry L. , Sorrell Ryan , Brown George S.
Published: December 2004

A number of systems provide feedback regarding client progress and experience of the therapeutic alliance to clinicians. Available evidence indicates that access to such data improves retention and outcome for clients most at risk for treatment failure. Over the last several years, the team at the Institute for the Study of Therapeutic Change has worked to develop an outcome management system that not only provides valid and reliable feedback, but also is as user‐friendly as possible for therapists and consumers. In this article, we describe the system and summarize current research findings. © 2004 Wiley Periodicals, Inc. J Clin Psychol/In Session.