bluuebunny/crossref_metadata_2025_split huggingface dataset:
Frequent 7q gains in flow cytometric multiploid/hypertetraploid breast carcinomas: a study of chromosome imbalances by comparative genomic hybridisation
Authors: Pinto A E , Roque L , Rodrigues R , André S , Soares J 
Published: February 2006

Objective:To investigate underlying genetic events associated with complex DNA ploidy breast carcinomas.Methods:Screening for chromosome imbalances was carried out using comparative genomic hybridisation (CGH) in 14 frozen samples of tumour from a series of 13 breast cancer patients with multiploid (n = 11) and hypertetraploid (n = 2) tumours. They had previously been analysed by DNA flow cytometry and also assessed immunohistochemically for p53 tissue expression. Ploidy status was determined on frozen samples using the Multicycle software program.Results:The total number of copy gains (n = 242) was significantly greater than the number of copy losses (n = 51). The mean (SD) number of gains per sample was 17.3 (5.7), and of losses, 3.6 (4.2) (p = 0.0001). Gains of chromosomal regions at 1q (14/14; 100%), 7q (12/14; 85.7%), and 3q (11/14; 78.6%), as well as 1p, 2q, 5p, 8q, and 13q (10/14; 71.4%) were the most frequent aberrations in this series. Losses were most commonly found on 17p (5/14; 35.7%). Three patients dying of the disease had tumours with high level amplifications at 1q12-qter, 3q22–q25, and 8q22–q23 regions. Six cases had p53 overexpression, of whom four showed 12q gains and two showed 17p losses.Conclusions:There is a very high incidence of genetic aberrations, mainly related to chromosomal gains, in this subgroup of aneuploid breast cancer patients, associated with a poor clinical outcome. The 7q locus, not previously reported as showing frequent changes in breast cancer, was found to be a potential site for some candidate oncogenes.
Pitfalls in immunohistochemical assessment of EGFR expression in soft tissue sarcomas
Authors: Kersting C , Packeisen J , Leidinger B , Brandt B , von Wasielewski R , Winkelmann W , van Diest P J , Gosheger G , Buerger H 
Published: February 2006

Background:New targeted cancer treatments acting against growth factor receptors such as the epidermal growth factor receptor (EGFR) necessitate selecting patients for treatment with these drugs. Besides carcinomas, soft tissue sarcomas (STS) express EGFR and might thereby be a promising target for this new therapeutic strategy.Objective:To test and compare different EGFR antibodies to determine the frequency of EGFR expression in STS.Methods:302 consecutive specimens of STS were examined using the tissue microarray technique. EGFR expression levels were assessed by immunohistochemistry using five different commercially available antibodies. Gene amplification status was measured by fluorescence in situ hybridisation (FISH). Immunoreactivity and amplification status were correlated with clinicopathological features and follow up data available in 163 cases.Results:EGFR expression frequency ranged between 0.3% and 52.9%, depending on the antibody and scoring method used. In all, 3.5% of the tumours showedegfrgene amplification by FISH, which correlated with EGFR expression for three antibodies. Only one antibody had independent prognostic value in multivariate analysis and correlated with an unfavourable outcome;egfrgene amplification status showed no correlation with clinical features.Conclusions:Frequency of EGFR immunopositivity in STS strongly depends on the antibody used, and only one of five antibodies tested predicted an unfavourable clinical outcome. This indicates that choice of primary antibody and scoring system have a substantial impact on the determination of EGFR immunoreactivity.
Renal medullary changes in renal allograft recipients with raised serum creatinine
Authors: Sis B , Sarioglu S , Celik A , Kasap B , Yildiz S , Kavukcu S , Gulay H , Camsari T 
Published: February 2006

Objective:To test the hypothesis that the renal medulla may reflect rejection related changes and thus have a predictive value in the assessment of acute renal allograft rejection or chronic graft damage.Methods:75 post-transplant biopsies from 57 patients were scored according to the Banff 1997 scheme. The biopsies with adequate cortical and medullary tissue (n = 23) were selected and medullary tissues were reviewed for rejection related lesions except intimal arteritis. Chronic damage was determined by image analysis depending on periodic acid-methenamine silver (PAMS)-Masson trichrome (MT) staining. Medullary and cortical changes were compared.Results:Interstitial inflammation and tubulitis were more frequent and severe in the cortex (p<0.001). Medullary tubulitis was associated with intimal arteritis (p = 0.003,r = 0.598). Medullary interstitial inflammation (n = 8) and tubulitis (n = 4) were associated with cortical borderline changes (n = 5) or allograft rejection (n = 3). The sensitivity, specificity, and positive and negative predictive values of medullary inflammatory changes in predicting cortical allograft rejection were 43%, 69%, 37%, and 73%, respectively. A significant association was observed between medullary MT-SAP and cortical PAMS-SAP values (p = 0.02,R2 = 0.23).Conclusions:Acute rejection related lesions are more common and severe in the cortex, and the renal medulla does not sufficiently reflect cortical rejection. The positive and negative predictive values of medullary changes for allograft rejection are low, and medullary inflammation is not a reliable indicator of allograft rejection. Increased medullary fibrosis is correlated with chronic cortical damage.
Enumeration and immunohistochemical characterisation of bone marrow basophils in myeloproliferative disorders using the basophil specific monoclonal antibody 2D7
Authors: Agis H , Krauth M-T , Mosberger I , Müllauer L , Simonitsch-Klupp I , Schwartz L B , Printz D , Böhm A , Fritsch G , Horny H-P , Valent P 
Published: February 2006

Background:Basophils are highly specialised granulocytes that express a unique profile of antigens and increase in myeloproliferative disorders (MPD). In chronic myeloid leukaemia (CML), basophilia is a diagnostic and prognostic determinant. So far, however, no reliable approach for routine detection and enumeration of bone marrow basophils has become available.Objective:To detect and enumerate basophils in bone marrow sections in patients with CML and other MPDMethods:The anti-basophil antibody 2D7 was applied to paraffin embedded bone marrow sections from normal/reactive subjects (n = 31), patients with CML (chronic phase, n = 37; accelerated phase, n = 9), and other MPD (chronic idiopathic myelofibrosis (CIMF), n = 20; polycythaemia vera (PV), n = 20; essential thrombocythaemia (ET), n = 20; indolent systemic mastocytosis (ISM), n = 7).Results:As assessed by serial section staining, 2D7+cells were found to co-express myeloperoxidase, histidine decarboxylase, CD9, and CD43, but did not express B cell or T cell restricted antigens. 2D7+bone marrow cells were found to increase in CML compared with normal/reactive bone marrow and other MPD (median numbers of 2D7+cells/mm2: CML, 33; normal/reactive bone marrow, 6; CIMF, 10; PV, 6; ET, 5; ISM, 3; p<0.05). The highest basophil counts were recorded in accelerated phase CML (115/mm2).Conclusions:A novel immunohistochemical procedure has been established for basophil detection in normal bone marrow and MPD. This approach should help in the quantification of bone marrow basophils at diagnosis and during anti-leukaemic treatment.
Prognostic significance of E-cadherin–catenin complex in epithelial ovarian cancer
Authors: Voutilainen K A , Anttila M A , Sillanpää S M , Ropponen K M , Saarikoski S V , Juhola M T , Kosma V-M 
Published: February 2006

Objective:To clarify the prognostic role of E-cadherin and β- and γ-catenins, and their relation to CD44 in epithelial ovarian carcinoma.Methods:The expression of E-cadherin and β- and γ-catenins was analysed immunohistochemically in 305 primary epithelial ovarian cancers and 44 metastases, and related to CD44 expression, clinicopathological factors, and the patients’ survival.Results:Reduced cell surface expression of E-cadherin, β-catenin, and γ-catenin was particularly frequent in serous and endometrioid histological types. Reduced cell surface expression of E-cadherin and β-catenin was also associated with poor differentiation. Nuclear positivity of β-catenin was associated with high CD44 expression, endometrioid histology, and local stage of the tumour, whereas nuclear γ-catenin expression was associated with serous histology and poor differentiation. In the univariate analysis, preserved cell surface β-catenin expression in the whole study material and nuclear expression of β- and γ-catenins in the subgroup of endometrioid ovarian cancers were predictors of better 10 year disease related survival. Preserved cell surface expression of E-cadherin and β-catenin predicted favourable recurrence-free survival. These statistical significances were not retained in multivariate analysis.Conclusions:The correlation between nuclear β-catenin and CD44 indicates that β-catenin may regulate the transcription of CD44 in epithelial ovarian cancer. E-cadherin–catenin complex members are associated with the prognosis of patients with epithelial ovarian cancer, but these univariate associations were not strong enough to compete for significance with the traditional clinicopathological factors.
Computerised pathology test order entry reduces laboratory turnaround times and influences tests ordered by hospital clinicians: a controlled before and after study
Authors: Westbrook J I , Georgiou A , Dimos A , Germanos T 
Published: February 2006

Objective:To assess the impact of a computerised pathology order entry system on laboratory turnaround times and test ordering within a teaching hospital.Methods:A controlled before and after study compared test assays ordered from 11 wards two months before (n = 97 851) and after (n = 113 762) the implementation of a computerised pathology order entry system (Cerner Millennium Powerchart). Comparisons were made of laboratory turnaround times, frequency of tests ordered and specimens taken, proportions of patients having tests, average number per patient, and percentage of gentamicin and vancomycin specimens labelled as random.Results:Intervention wards experienced an average decrease in turnaround of 15.5 minutes/test assay (range 73.8 to 58.3 minutes; p<0.001). Reductions were significant for prioritised and non-prioritised tests, and for those done within and outside business hours. There was no significant change in the average number of tests (p = 0.228), or specimens per patient (p = 0.324), and no change in turnaround time for the control ward (p = 0.218). Use of structured order screens enhanced data provided to laboratories. Removing three test assays from the liver function order set resulted in significantly fewer of these tests being done.Conclusions:Computerised order entry systems are an important element in achieving faster test results. These systems can influence test ordering patterns through structured order screens, manipulation of order sets, and analysis of real time data to assess the impact of such changes, not possible with paper based systems. The extent to which improvements translate into improved patient outcomes remains to be determined. A potentially limiting factor is clinicians’ capacity to respond to, and make use of, faster test results.
Phosphohistone H3 labelling for histoprognostic grading of breast adenocarcinomas and computer-assisted determination of mitotic index
Authors: Bossard C , Jarry A , Colombeix C , Bach-Ngohou K , Moreau A , Loussouarn D , Mosnier J-F , Laboisse C L 
Published: February 2006

Background:Microscopic evaluation of mitotic figures is a routine procedure in the assessment of the histoprognostic grade of tumours. Nevertheless, their count may be fraught with difficulties. As histone H3 phosphorylation at serine 10 is closely linked to chromosomal condensation, a new monoclonal antibody directed to phosphorylated histone H3 (PPH3) was recently proposed to detect mitotic cells.Aim:To test the reliability of this antibody in detecting and counting mitotic figures in sections of breast adenocarcinomas, because of the importance of mitotic count in histoprognostic grading.Methods:The pattern of PPH3 staining in formalin-fixed paraffin wax-embedded tissues, including normal tissues and a series of 39 breast adenocarcinomas, was examined. A new computer-assisted method was also developed for determining the mitotic index.Results and conclusions:In all tissues tested, PPH3-labelled mitotic figures were easily detected, allowing a rapid identification of the area of highest mitotic activity. In breast carcinomas, a strong correlation was observed between PPH3-stained and haematoxylin and eosin-stained mitotic counts (r = 0.86, p<0.0001). Counting of prophase nuclei that coexpress cyclin B1, a marker of the G2/M phase, was possible by PPH3 staining; its accuracy led us to reconsider the tumour grade in three cases. Finally, an automatic computer-assisted method was designed for assessing mitotic index with confocal microscopy and image-analysis software.
Activity of the Dual Kinase Inhibitor Lapatinib (GW572016) against HER-2-Overexpressing and Trastuzumab-Treated Breast Cancer Cells
Authors: Konecny Gottfried E. , Pegram Mark D. , Venkatesan Natarajan , Finn Richard , Yang Guorong , Rahmeh Martina , Untch Michael , Rusnak David W. , Spehar Glenn , Mullin Robert J. , Keith Barry R. , Gilmer Tona M. , Berger Mark , Podratz Karl C. , Slamon Dennis J. 
Published: February 2006

Abstract
Lapatinib (GW572016) is a selective inhibitor of both epidermal growth factor receptor (EGFR) and HER-2 tyrosine kinases. Here, we explore the therapeutic potential of lapatinib by testing its effect on tumor cell growth in a panel of 31 characterized human breast cancer cell lines, including trastuzumab-conditioned HER-2-positive cell lines. We further characterize its activity in combination with trastuzumab and analyze whether EGFR and HER-2 expression or changes induced in the activation of EGFR, HER-2, Raf, AKT, or extracellular signal-regulated kinase (ERK) are markers of drug activity. We report that concentration-dependent antiproliferative effects of lapatinib were seen in all breast cancer cell lines tested but varied significantly between individual cell lines with up to 1,000-fold difference in the IC50s (range, 0.010-18.6 μmol/L). Response to lapatinib was significantly correlated with HER-2 expression and its ability to inhibit HER-2, Raf, AKT, and ERK phosphorylation. Long-term in vivo lapatinib studies were conducted with human breast cancer xenografts in athymic mice. Treatment over 77 days resulted in a sustained and significant reduction in xenograft volume compared with untreated controls. For the combination of lapatinib plus trastuzumab, synergistic drug interactions were observed in four different HER-2-overexpressing cell lines. Moreover, lapatinib retained significant in vitro activity against cell lines selected for long-term outgrowth (&gt;9 months) in trastuzumab-containing (100 μg/mL) culture medium. These observations provide a clear biological rationale to test lapatinib as a single agent or in combination with trastuzumab in HER-2-overexpressing breast cancer and in patients with clinical resistance to trastuzumab. (Cancer Res 2006; 66(3): 1630-9)
Soy Phytochemicals Prevent Orthotopic Growth and Metastasis of Bladder Cancer in Mice by Alterations of Cancer Cell Proliferation and Apoptosis and Tumor Angiogenesis
Authors: Singh Ajita V. , Franke Adrian A. , Blackburn George L. , Zhou Jin-Rong 
Published: February 2006

Abstract
A role of dietary bioactive components in bladder cancer prevention is biologically plausible because most substances or metabolites are excreted through the urinary tract and are consequently in direct contact with the mucosa of the bladder. We first determined antigrowth activity of genistein against poorly differentiated 253J B-V human bladder cancer cells in vitro. Genistein inhibited the cell growth in a time- and dose-dependent manner via G2-M arrest, down-regulation of nuclear factor κB (NF-κB), and induction of apoptosis. We also evaluated both genistin, which is a natural form of genistein, and the isoflavone-rich soy phytochemical concentrate (SPC) on the growth and metastasis of 253J B-V tumors in an orthotopic tumor model. Mice treated with genistin and SPC had reduced final tumor weights by 56% (P &lt; 0.05) and 52% (P &lt; 0.05), respectively, associated with induction of tumor cell apoptosis and inhibition of tumor angiogenesis in vivo. In addition, SPC treatment, but not genistin treatment, significantly inhibited lung metastases by 95% (P &lt; 0.01) associated with significant down-regulation of NF-κB expression in tumor tissues and reduction of circulating insulin-like growth factor-I levels, suggesting that SPC may contain other bioactive ingredients that have antimetastatic activity. The results from our studies suggest that further clinical investigation should be warranted to apply soy phytochemicals, such as SPC, as a potent prevention regimen for bladder cancer progression. This orthotopic human bladder tumor model also provides a clinically relevant experimental tool for assessing potential preventive activity of other dietary components against bladder tumor growth and metastasis. (Cancer Res 2006; 66(3): 1851-8)
Transcriptional Repression of Telomerase RNA Gene Expression by c-Jun-NH2-Kinase and Sp1/Sp3
Authors: Bilsland Alan E. , Stevenson Katrina , Atkinson Stuart , Kolch Walter , Keith W. Nicol 
Published: February 2006

Abstract
Telomerase is essential for immortalization of most human cancer cells. Expression of the core telomerase RNA (hTR) and reverse transcriptase (hTERT) subunits is mainly regulated by transcription. However, hTR transcriptional regulation remains poorly understood. We previously showed that the core hTR promoter is activated by Sp1 and is repressed by Sp3. Here, we show that the mitogen-activated protein kinase kinase kinase 1 (MEKK1)/c-Jun-NH2-kinase (JNK) pathway represses hTR expression by a mechanism that involves Sp1 and Sp3. Promoter activity was induced by the JNK inhibitor SP600125 and was repressed by activated MEKK1. Repression by MEKK1 was blocked by SP600125 or enhanced by coexpression of wild-type but not phosphoacceptor mutated JNK. SP600125 treatment also increased levels of endogenous hTR. Mutations in the hTR promoter Sp1/Sp3 binding sites attenuated SP600125-mediated promoter induction, whereas coexpression of MEKK1 with Sp3 enhanced hTR promoter repression. Chromatin immunoprecipitation showed that levels of immunoreactive Sp1 associated with the hTR promoter were low in comparison with Sp3 in control cells but increased after JNK inhibition with a reciprocal decrease in Sp3 levels. No corresponding changes in Sp1/Sp3 protein levels were detected. Thus, JNK represses hTR promoter activity and expression, apparently by enhancing repression through Sp3. (Cancer Res 2006; 66(3): 1363-70)
Red Meat Enhances the Colonic Formation of the DNA Adduct O6-Carboxymethyl Guanine: Implications for Colorectal Cancer Risk
Authors: Lewin Michelle H. , Bailey Nina , Bandaletova Tanya , Bowman Richard , Cross Amanda J. , Pollock Jim , Shuker David E.G. , Bingham Sheila A. 
Published: February 2006

Abstract
Red meat is associated with increased risk of colorectal cancer and increases the endogenous formation of N-nitrosocompounds (NOC). To investigate the genotoxic effects of NOC arising from red meat consumption, human volunteers were fed high (420 g) red meat, vegetarian, and high red meat, high-fiber diets for 15 days in a randomized crossover design while living in a volunteer suite, where food was carefully controlled and all specimens were collected. In 21 volunteers, there was a consistent and significant (P &lt; 0.0001) increase in endogenous formation of NOC with the red meat diet compared with the vegetarian diet as measured by apparent total NOC (ATNC) in feces. In colonic exfoliated cells, the percentage staining positive for the NOC-specific DNA adduct, O6-carboxymethyl guanine (O6CMG) was significantly (P &lt; 0.001) higher on the high red meat diet. In 13 volunteers, levels were intermediate on the high-fiber, high red meat diet. Fecal ATNC were positively correlated with the percentage of cells staining positive for O6CMG (r2 = 0.56, P = 0.011). The presence of O6CMG was also shown in intact small intestine from rats treated with the N-nitrosopeptide N-acetyl-N′-prolyl-N′-nitrosoglycine and in HT-29 cells treated with diazoacetate. This study has shown that fecal NOC arising from red meat include direct acting diazopeptides or N-nitrosopeptides able to form alkylating DNA adducts in the colon. As these O6CMG adducts are not repaired, and if other related adducts are formed and not repaired, this may explain the association of red meat with colorectal cancer. (Cancer Res 2006; 66(3): 1859-65)
Characterization of a von Hippel Lindau Pathway Involved in Extracellular Matrix Remodeling, Cell Invasion, and Angiogenesis
Authors: Kurban Ghada , Hudon Valérie , Duplan Eric , Ohh Michael , Pause Arnim 
Published: February 2006

Abstract
Inactivation of the von Hippel-Lindau (VHL) tumor suppressor gene results in highly vascularized tumors, making the VHL tumor syndrome an ideal system to study the mechanisms of angiogenesis. VHL operates along two pathways with the first involving hypoxia-inducible factor-α degradation and down-regulation of its proangiogenic target genes vascular endothelial growth factor and platelet-derived growth factor-β, and the second pathway promoting extracellular matrix (ECM) assembly. Secretion of proangiogenic factors was shown to be a primary inducer of angiogenesis. Here, we show that loss of ECM assembly correlates with tumor angiogenesis in VHL disease. Upon inactivation of the VHL-ECM assembly pathway, we observe tumors that are highly vascularized, have a disrupted ECM, and show increased matrix metalloproteinase-2 activity. Loss of the VHL pathway leading to hypoxia-inducible factor-α degradation results in tumors with increased vascular endothelial growth factor levels but with surprisingly low microvessel density, a tightly assembled ECM and low invasive ability. We conclude that loss of ECM integrity could promote and maintain tumor angiogenesis by providing a route for blood vessels to infiltrate tumors. (Cancer Res 2006; 66(3): 1313-9)