bluuebunny/crossref_metadata_2025_split huggingface dataset:
Prognostic significance of p21WAF1/CIP1, p27Kip1, p53 and E-cadherin expression in gastric cancer
Authors: Gamboa-Dominguez Armando , Seidl Stefan , Reyes-Gutierrez Edgardo , Hermannstädter Christine , Quintanilla-Martinez Leticia , Busch Raymonde , Höfler Heinz , Fend Falko , Luber Birgit 
Published: May 2007

Background:Gastric carcinoma is characterised by numerous genetic and epigenetic alterations that influence cell cycle progression, apoptosis and DNA repair. These alterations include down-regulation of the cyclin-dependent kinase (CDK) inhibitors p21WAF1/CIP1and p27Kip1, and mutations of the tumour suppressor protein p53 and the cell adhesion molecule E-cadherin. Combined evaluation of the prognostic significance of these alterations has not been reported in Mexican Mestizo patients.Aims:To evaluate p21WAF1/CIP1, p27Kip1, p53 and E-cadherin protein expression, including mutant E-cadherin variants with deletion of exon 8 (del 8) or 9 (del 9), in gastric cancer from Mexican patients.Methods:Immunohistochemistry for the above-mentioned markers, including mutation-specific E-cadherin antibodies, was carried out in 69 gastric carcinomas; expression levels were correlated with histotype, tumour stage and prognosis.Results:Expression of p21WAF1/CIP1alone or in combination with p27Kip1or in the absence of p53 was associated with favourable prognosis. Staining ofdel 8anddel 9E-cadherin was found exclusively in patients negative for p53 and positive for p21WAF1/CIP1, suggesting that the p21WAF1/CIP1regulatory function of p53 was intact.Conclusion:Combined evaluation of the prognostic significance of cell cycle regulators and E-cadherin should be performed. Even though patients negative for p53 and positive for p21WAF1/CIP1have a favourable prognosis, it may have a negative influence on prognosis if they acquire in addition E-cadherin mutations which have been shown previously to be associated with poor survival.
Progressive derailment of cell cycle regulators in endometrial carcinogenesis
Authors: Horrée N , van Diest P J , van der Groep P , Sie-Go D M D S , Heintz A P M 
Published: May 2007

Background:Derailments of the control mechanisms of the cell cycle can initiate carcinogenesis, and play a role in progression to cancer.Aim:To explore the expression of cell cycle proteins in normal, premalignant and malignant endometrial lesions representing the morphologically well defined stepwise model of human endometrial carcinogenesisMethods:Observational study. Paraffin-embedded specimens from inactive endometrium (n = 16), endometrial hyperplasia (n = 23) and endometrioid endometrial carcinoma (n = 39) were stained immunohistochemically for cyclin A, cyclin B1, cyclin D1, cyclin E, cdk2, p16, p21, p27, p53 and Ki67(MIB-1)). Differences in expression between the tissues, and correlation with classical prognostic factors for the carcinomas were analysed.Results:Expression of cyclin A and Ki67 gradually increased from normal through hyperplasia to carcinoma, indicating that proliferation increases over the carcinogenetic spectrum. cdk2, p16 and p21 gradually increased from normal through hyperplasia to carcinoma, indicating their potential importance in both early and late carcinogenesis. Cyclin D1, cyclin E and p53 especially increased and p27 decreased from hyperplasia to carcinoma, underlining their role in late carcinogenesis. In cancers, expression of cyclin A, p53 and Ki67 was positively correlated to grade, and cyclin A was positively correlated with cdk2, p21, Ki67, cyclin E and p53.Conclusion:During (endometrioid) endometrial carcinogenesis, there is increasing proliferation paralleled by progressive derailment of cyclin B1, cyclin D1, cyclin E, p16, p21, p27, p53, and cdk2, indicating the importance of these cell cycle regulators in endometrial carcinogenesis.
Immune factors involved in the cervical immune response in the HIV/HPV co-infection
Authors: Nicol A F , Nuovo G J , Salomão-Estevez A , Grinsztein B , Tristão A , Russomano F , Lapa e Silva J R , Oliveira M P , Pirmez C 
Published: May 2007

Aims:Immune factors influencing the progression of cervical intraepithelial neoplasia (CIN) to cancer remain poorly defined. This study investigates the expression of RANTES, MIP1α, COX1, COX2, STAT3, TGFβRI, IL10R, TNFαRII and TLR4 in the cervical immune response in HIV/HPV (human papillomavirus) co-infected women.Methods:Cervical biopsies of 36 patients were assayed by immunohistochemistry, and the Ventana Benchmark System was used for HIV-nef detection.Results:Cervices from HIV-positive patients exhibited nef in cells mainly around blood vessels, and showed a decreased expression of all the immune factors tested except IL10R and STAT3, while RANTES (5.54 cells/mm2) was highly expressed in comparison with controls (1.41 cells/mm2, p = 0.028). COX1 was decreased in the HIV/HPV- (0.32 cells/mm2, p = 0.017) and HPV-infected patients (0.21 cells/mm2, p = 0.015) compared with controls (3.28 cells/mm2).Conclusions:It is suggested that RANTES in HIV/HPV co-infection may influence the development of CIN leading to progression to cervical cancer.
Cyclin E confers a prognostic value in premenopausal breast cancer patients with tumours exhibiting an infiltrative growth pattern
Authors: Berglund P , Stighall M , Jirström K , Rydén L , Fernö M , Nordenskjöld B , Landberg G 
Published: May 2007

Aims:To investigate the prognostic value of cyclin E in relation to tumour growth pattern by analysing stage II primary breast cancers from premenopausal women not subjected to any further adjuvant treatment. To analyse the value of cyclin E as a predictor of tamoxifen response, by comparing untreated and treated patients with oestrogen receptor positive tumours.Methods:Breast cancer samples, assembled in tissue microarrays, were immunohistochemically stained for cyclin E and evaluated regarding the presence of nuclear staining. The overall growth characteristics of each tumour were assessed using whole tissue sections.Results:Tumours displaying a pushing margin phenotype were strongly associated with high cyclin E levels, lymph node negative disease, a high histological grade and oestrogen receptor negativity, and exhibited a better prognosis compared to tumours with an infiltrative growth pattern. In the total cohort of non-treated patients (n = 187), cyclin E was not associated with recurrence free survival (RFS). However, when analysing the subgroup of tumours lacking a pushing growth pattern (n = 141), cyclin E was significantly associated with RFS, independent of histological grade and node status. There was no significant difference in tamoxifen response with regard to different cyclin E levels.Conclusion:The prognostic value of cyclin E in premenopausal breast cancer is limited to patients with breast carcinomas exhibiting an exclusively infiltrative growth pattern. This limitation could be explained by the presence of a small but distinct subgroup of cyclin E-high breast cancers with a pushing margin phenotype and a more favourable outcome.
Development of two novel benzoylphenylurea sulfur analogues and evidence that the microtubule-associated protein tau is predictive of their activity in pancreatic cancer
Authors: Jimeno Antonio , Hallur Gurulingappa , Chan Audrey , Zhang Xiangfeng , Cusatis George , Chan Fonda , Shah Preeti , Chen Rongbing , Hamel Ernest , Garrett-Mayer Elizabeth , Khan Saeed , Hidalgo Manuel 
Published: May 2007

Abstract
In this work, we evaluated two lead compounds, referred to as SG410 and SG430, obtained from a screen of sulfur benzoylphenylurea analogues, against in vitro and in vivo models of pancreas cancer. Both drugs showed a similar mechanism of action profile, with SG410 being more potent as an inhibitor of tubulin assembly. We determined the best in vivo administration schedule and tested SG410 and SG430 in nine cases of a novel platform of direct pancreas cancer xenografts. Both compounds had antiproliferative activity in vitro in the low nanomolar range, but only SG410 showed significant activity in vivo. Administration of SG410 resulted in significant tumor growth delay in five of nine groups tested. In a direct comparison in three of the cases, SG410 was at least as efficacious as docetaxel. We also sought markers that would be predictive of the efficacy of these agents, and we found such a marker in microtubule-associated protein tau (MAPT). This protein enhances the assembly and stability of microtubules. In both the cell lines and the direct human xenografts, MAPT mRNA and protein levels correlated well. There was also a statistically significant inverse correlation between MAPT expression and sensitivity to the tested agents. In summary, the novel sulfur benzoylphenylurea SG410 showed activity inversely related to MAPT expression in a preclinical model of pancreatic cancer comparable with that observed with docetaxel, another microtubule-targeting agent. [Mol Cancer Ther 2007;6(5):1509–16]
Differential regulation of vascular endothelial growth factor by Akt and mammalian target of rapamycin inhibitors in cell lines derived from childhood solid tumors
Authors: Kurmasheva Raushan T. , Harwood Franklin C. , Houghton Peter J. 
Published: May 2007

Abstract
Levels of vascular endothelial growth factor (VEGF) are regulated, in part, through activation of the phosphatidylinositol 3′-kinase/Akt pathway. Using pharmacologic inhibitors, we have examined the relative contributions of Akt and mammalian target of rapamycin (mTOR) signaling to VEGF production in neuroblastoma and rhabdomyosarcoma cells growing under normoxic (21% O2) or hypoxic (1% O2) conditions. Exogenous VEGF stimulated both Akt and extracellular signal–regulated kinase 1/2 phosphorylation in six of seven rhabdomyosarcoma cell lines but in only one of seven neuroblastoma cells, suggesting autocrine stimulation predominantly in rhabdomyosarcoma cell lines. In general, under normoxic conditions, neuroblastoma cells produced more VEGF (120–1,180 pg/106 cells/24 h) compared with rhabdomyosarcoma lines (0–200 pg/106 cells/24 h). Rapamycin, a selective inhibitor of mTOR, reduced VEGF production in rhabdomyosarcoma cells under normoxic conditions and partially suppressed hypoxia-driven increases in VEGF. However, it poorly inhibited VEGF production under either condition in the majority of neuroblastoma cell lines despite inhibition of mTOR signaling. Rapamycin failed to modulate levels of hypoxia-inducible factor 1α (HIF-1α) under normoxic conditions and modestly reduced hypoxia-driven increases in HIF-1α only in rhabdomyosarcoma cells. In contrast to rapamycin, inhibition of Akt by A-443654 completely blocked signaling to glycogen synthase kinase 3β and had more dramatic effects on VEGF production. Notably, A-443654 significantly inhibited VEGF production in rapamycin-refractory neuroblastoma cell lines. Importantly, whereas combining A-443654 with rapamycin had variable effect on cell proliferation, the combination essentially blocked hypoxia-driven increases in VEGF in all cell lines examined, suggesting that dual blockade at different levels in the phosphatidylinositol 3′-kinase–initiated signaling pathway may be a reasonable strategy for preventing VEGF production in cancer cells derived from pediatric solid tumors. However, this will require formal testing in vivo using animal models of childhood cancer. [Mol Cancer Ther 2007;6(5):1620–8]
Defining regional infusion treatment strategies for extremity melanoma: comparative analysis of melphalan and temozolomide as regional chemotherapeutic agents
Authors: Yoshimoto Yasunori , Augustine Christina K. , Yoo Jin S. , Zipfel Patricia A. , Selim M. Angelica , Pruitt Scott K. , Friedman Henry S. , Ali-Osman Francis , Tyler Douglas S. 
Published: May 2007

Abstract
Five different human melanoma xenografts were used in a xenograft model of extremity melanoma to evaluate the variability of tumor response to regionally administered melphalan or temozolomide and to determine if various components of pertinent drug resistance pathways for melphalan [glutathione S-transferase (GST)/glutathione] and temozolomide [O6-alkylguanine DNA alkyltranferase (AGT)/mismatch repair (MMR)] could be predictive of tumor response. Xenograft-bearing rats underwent regional isolated limb infusion with either melphalan (90 mg/kg) or temozolomide (2,000 mg/kg). The levels of AGT activity, GST activity, glutathione level, and GST/AGT expression were examined in this group of xenografts and found to be quite heterogeneous. No correlation was identified between melphalan sensitivity and the GST/glutathione cellular detoxification pathway. In contrast, a strong correlation between the levels of AGT activity and percentage increase in tumor volume on day 30 (r = 0.88) was noted for tumors treated with temozolomide. Regional therapy with temozolomide was more effective when compared with melphalan for the xenograft with the lowest AGT activity, whereas melphalan was more effective than temozolomide in another xenograft that had the highest AGT activity. In three other xenografts, there was no significant difference in response between the two chemotherapy agents. This study shows that AGT activity may be useful in predicting the utility of temozolomide-based regional therapy for advanced extremity melanoma tumors. Our observations also point out the limited ability of analysis of the GST/glutathione pathway to predict response to chemotherapies like melphalan whose resistance is primarily mediated through a complex mechanism of detoxification. [Mol Cancer Ther 2007;6(5):1492–500]
MicroRNA expression profiles for the NCI-60 cancer cell panel
Authors: Blower Paul E. , Verducci Joseph S. , Lin Shili , Zhou Jin , Chung Ji-Hyun , Dai Zunyan , Liu Chang-Gong , Reinhold William , Lorenzi Philip L. , Kaldjian Eric P. , Croce Carlo M. , Weinstein John N. , Sadee Wolfgang 
Published: May 2007

Abstract
Advances in the understanding of cancer cell biology and response to drug treatment have benefited from new molecular technologies and methods for integrating information from multiple sources. The NCI-60, a panel of 60 diverse human cancer cell lines, has been used by the National Cancer Institute to screen &gt;100,000 chemical compounds and natural product extracts for anticancer activity. The NCI-60 has also been profiled for mRNA and protein expression, mutational status, chromosomal aberrations, and DNA copy number, generating an unparalleled public resource for integrated chemogenomic studies. Recently, microRNAs have been shown to target particular sets of mRNAs, thereby preventing translation or accelerating mRNA turnover. To complement the existing NCI-60 data sets, we have measured expression levels of microRNAs in the NCI-60 and incorporated the resulting data into the CellMiner program package for integrative analysis. Cell line groupings based on microRNA expression were generally consistent with tissue type and with cell line clustering based on mRNA expression. However, mRNA expression seemed to be somewhat more informative for discriminating among tissue types than was microRNA expression. In addition, we found that there does not seem to be a significant correlation between microRNA expression patterns and those of known target transcripts. Comparison of microRNA expression patterns and compound potency patterns showed significant correlations, suggesting that microRNAs may play a role in chemoresistance. Combined with gene expression and other biological data using multivariate analysis, microRNA expression profiles may provide a critical link for understanding mechanisms involved in chemosensitivity and chemoresistance. [Mol Cancer Ther 2007;6(5):1483–91]
p53 therapy in a patient with Li-Fraumeni syndrome
Authors: Senzer Neil , Nemunaitis John , Nemunaitis Michael , Lamont Jeffrey , Gore Martin , Gabra Hani , Eeles Rosalind , Sodha Nayanta , Lynch Frank J. , Zumstein Louis A. , Menander Kerstin B. , Sobol Robert E. , Chada Sunil 
Published: May 2007

Abstract
Li-Fraumeni syndrome is an autosomal dominant disorder that greatly increases the risk of developing multiple types of cancer. The majority of Li-Fraumeni syndrome families contain germ-line mutations in the p53 tumor suppressor gene. We describe treatment of a refractory, progressive Li-Fraumeni syndrome embryonal carcinoma with a p53 therapy (Advexin) targeted to the underlying molecular defect of this syndrome. p53 treatment resulted in complete and durable remission of the injected lesion by fluorodeoxyglucose-positron emission tomography scans with improvement of tumor-related symptoms. With respect to molecular markers, the patient's tumor had abnormal p53 and expressed coxsackie adenovirus receptors with a low HDM2 and bcl-2 profile conducive for adenoviral p53 activity. p53 treatment resulted in the induction of cell cycle arrest and apoptosis documented by p21 and cleaved caspase-3 detection. Increased adenoviral antibody titers after repeated therapy did not inhibit adenoviral p53 activity or result in pathologic sequelae. Relationships between these clinical, radiographic, and molecular markers may prove useful in guiding future application of p53 tumor suppressor therapy. [Mol Cancer Ther 2007;6(5):1478–1482
Functional deficiencies of granulocyte-macrophage colony stimulating factor and interleukin-3 contribute to insulitis and destruction of β cells
Authors: Enzler Thomas , Gillessen Silke , Dougan Michael , Allison James P. , Neuberg Donna , Oble Darryl A. , Mihm Martin , Dranoff Glenn 
Published: May 2007

AbstractThe pathogenesis of type 1 diabetes (T1D) involves the immune-mediated destruction of insulin-producing β cells in the pancreatic islets of Langerhans. Genetic analysis of families with a high incidence of T1D and nonobese diabetic (NOD) mice, a prototypical model of the disorder, uncovered multiple susceptibility loci, although most of the underlying immune defects remain to be delineated. Here we report that aged mice doubly deficient in granulocyte-macrophage colony-stimulating factor (GM-CSF) and interleukin-3 (IL-3) manifest insulitis, destruction of insulin-producing β cells, and compromised glucose homeostasis. Macrophages from mutant mice produce increased levels of p40 after LPS stimulation, whereas concurrent ablation of interferon-γ (IFN-γ) ameliorates the disease. The administration of antibodies that block cytotoxic T lymphocyte associated antigen-4 (CTLA-4) to young mutant mice precipitates the onset of insulitis and hyperglycemia. These results, together with previous reports of impaired hematopoietic responses to GM-CSF and IL-3 in patients with T1D and in NOD mice, indicate that functional deficiencies of these cytokines contribute to diabetes.
Genetic and pharmacologic evidence implicating the p85α, but not p85β, regulatory subunit of PI3K and Rac2 GTPase in regulating oncogenic KIT-induced transformation in acute myeloid leukemia and systemic mastocytosis
Authors: Munugalavadla Veerendra , Sims Emily C. , Borneo Jovencio , Chan Rebecca J. , Kapur Reuben 
Published: May 2007

AbstractOncogenic activation loop KIT mutations are observed in acute myeloid leukemia (AML) and systemic mastocytosis (SM); however, unlike the KIT juxtamembrane mutants, the activation loop mutants are insensitive to imatinib mesylate. Furthermore, as prior studies primarily used heterologous cell lines, the molecular mechanism(s) underlying oncogenic KIT-induced transformation in primary cells is poorly understood. We demonstrate that expression of KITD814V in primary hematopoietic stem/progenitor cells (HSC/Ps) and mast cell progenitors (MCps) induces constitutive KIT autophosphorylation, supports ligand-independent hyperproliferation, and promotes promiscuous cooperation with multiple cytokines. Genetic disruption of p85α, the regulatory subunit of class IA lipid kinase phosphoinositol-3-kinase (PI3K), but not of p85β, or genetic disruption of the hematopoietic cell-specific Rho GTPase, Rac2, normalizes KITD814V-induced ligand-independent hyperproliferation. Additionally, deficiency of p85α or Rac2 corrects the promiscuous hyperproliferation observed in response to multiple cytokines in both KITD814V-expressing HSC/Ps and MCps. Treatment of KITD814V-expressing HSC/Ps with a Rac inhibitor (NC23766) or with rapamycin showed a dose-dependent suppression in ligand-independent growth. Taken together, our results identify p85α and Rac2 as potential novel therapeutic targets for the treatment of KITD814V-bearing AML and SM.
Noncanonical NF-κB signaling in dendritic cells is required for indoleamine 2,3-dioxygenase (IDO) induction and immune regulation
Authors: Tas Sander W. , Vervoordeldonk Margriet J. , Hajji Najat , Schuitemaker Joost H. N. , van der Sluijs Koen F. , May Michael J. , Ghosh Sankar , Kapsenberg Martien L. , Tak Paul P. , de Jong Esther C. 
Published: May 2007

AbstractLigation of CD40 on dendritic cells (DCs) induces early production of inflammatory mediators via canonical NF-κB signaling, as well as late expression of the anti-inflammatory enzyme indoleamine 2,3-dioxygenase (IDO) via unknown signal transduction. By selective blocking of either the canonical NF-κB pathway using the NEMO-binding domain peptide or the noncanonical NF-κB pathway by small interfering RNA, we demonstrate that IDO expression requires noncanonical NF-κB signaling. Also, noncanonical NF-κB signaling down-regulates proinflammatory cytokine production in DCs. In addition, selective activation of the noncanonical NF-κB pathway results in noninflammatory DCs that suppress T-cell activation and promote the development of T cells with regulatory properties. These findings reveal an important role of the noncanonical NF-κB pathway in the regulation of immunity.
The Effects of Clinical Workload on Teaching in the Emergency Department
Authors: Kelly Sean P. , Shapiro Nathan , Woodruff Michael , Corrigan Kelly , Sanchez Leon D. , Wolfe Richard E. 
Published: May 2007

Background:Academic emergency physicians have expressed concern that increased clinical workload and overcrowding adversely affect clinical teaching. Objectives:To evaluate the influence of clinical workload and attending physicians' teaching characteristics on clinical teaching in the emergency department (ED). Methods:This was a prospective observational study using learner satisfaction assessment tools to evaluate bedside teaching. On days when a research assistant was available, all ED residents and attending physicians were queried. A total of 335 resident surveys were administered over nine months (89% response). Clinical workload was measured by perception and patient volume. Teaching quality and characteristics were rated on ten‐point scales. A linear mixed‐effects model was used to obtain adjusted impact estimates of clinical workload and teaching attributes on teaching scores while controlling for individual attending physicians' teaching ability and residents' grading tendencies. Results:No clinical workload parameter had a significant effect on teaching scores: residents' workload perception (β estimate, 0.024; p = 0.55), attending physicians' workload perception (β estimate, −0.05; p = 0.28), patient volume in patients per hour (β estimate, −0.010; p = 0.36), and shift type (β estimate, −0.19; p = 0.28). The individual attending physician effect was significant (p < 0.001) and adjusted in each case. In another model, the attending physicians' learning environment established (β estimate, 0.12; p = 0.005), clinical teaching skills (β estimate, 0.36; p < 0.001), willingness to teach (β estimate, 0.25; p < 0.001), and interpersonal skills (β estimate, 0.19; p < 0.001) affected teaching scores, but the attending physicians' availability to teach had no significant effect (β estimate, 0.007; p = 0.35). Conclusions:Clinical workload and attending physicians' availability had little effect on teaching scores. Attending physicians' clinical teaching skills, willingness to teach, interpersonal skills, and learning environment established were the important determinants of overall scores. Skilled instructors received higher scores, regardless of how busy they were.