bluuebunny/crossref_metadata_2025_split huggingface dataset:
Expression of Matrix Metalloproteinases and Their Inhibitors in Medulloblastomas and Their Prognostic Relevance
Authors: Özen Özlem , Krebs Bjarne , Hemmerlein Bernhard , Pekrun Arnulf , Kretzschmar Hans , Herms Jochen 
Published: September 2005

Abstract
Purpose and Experimental Design: The cellular mechanisms leading to metastatic disease in medulloblastoma (MB), the most common malignant brain tumor in childhood, are mainly unknown. Recently, however, the involvement of matrix metalloproteinases (MMPs) has been suggested. We examined the expression and localization of four MMPs—MMP-2 and -9, membrane-type 1 and 2 MMP (MT1- and MT2-MMP)—and correlated the data with those for their main inhibitors, tissue inhibitors of metalloproteinases (TIMP-1, -2, and -3), in 83 classical and 18 desmoplastic MBs.
Results: Independent of the histological subtype, MMP-2 expression was found in a small percentage of tumors, whereas MMP-9 and MT1- or MT2-MMP were expressed in &gt;75% of tumor samples. The expression of TIMP-1, -2, and -3, on the other hand, was found to depend on the histological subtype: TIMP-3 was often found in classical MB, whereas TIMP-2 was often expressed in desmoplastic MB (P = 0.007–0.001). In addition, both TIMP-3 and -2 correlated significantly with the expression of all studied metalloproteinases except MMP-2. TIMP-1, detected only in classical MB in a low percentage, was the only TIMP that correlated with the expression of MMP-2. Kaplan-Meier estimation revealed significantly reduced long-term survival of patients with strong MMP expression in tumor samples. In multivariate logistic regression analysis, however, the prognosis was significantly determined only by clinical parameters.
Conclusions: TIMP-3 and -2 expression is highly correlated with histological subtypes of MBs and strongly associated with the expression of certain MMPs. The expression of TIMPs and MMPs, however, does not determine prognosis independently of clinical parameters.
Epstein-Barr Virus and Cancer
Authors: Thompson Matthew P. , Kurzrock Razelle 
Published: September 2005

AbstractEBV was the first human virus to be directly implicated in carcinogenesis. It infects &gt;90% of the world’s population. Although most humans coexist with the virus without serious sequelae, a small proportion will develop tumors. Normal host populations can have vastly different susceptibility to EBV-related tumors as demonstrated by geographical and immunological variations in the prevalence of these cancers. EBV has been implicated in the pathogenesis of Burkitt’s lymphoma, Hodgkin’s disease, non-Hodgkin’s lymphoma, nasopharyngeal carcinoma, and lymphomas, as well as leiomyosarcomas arising in immunocompromised individuals. The presence of this virus has also been associated with epithelial malignancies arising in the gastric region and the breast, although some of this work remains in dispute. EBV uses its viral proteins, the actions of which mimic several growth factors, transcription factors, and antiapoptotic factors, to usurp control of the cellular pathways that regulate diverse homeostatic cellular functions. Recent advances in antiviral therapeutics, application of monoclonal antibodies, and generation of EBV-specific CTLs are beginning to show promise in the treatment of EBV-related disorders.
Macrophage Colony-Stimulating Factor-1 Receptor Expression Is Associated with Poor Outcome in Breast Cancer by Large Cohort Tissue Microarray Analysis
Authors: Kluger Harriet M. , Dolled-Filhart Marisa , Rodov Sofya , Kacinski Barry M. , Camp Robert L. , Rimm David L. 
Published: September 2005

AbstractPurpose: Macrophage colony-stimulating factor-1 receptor (CSF-1R) is a transmembrane tyrosine kinase receptor, which is abnormally expressed in invasive breast cancer. Small cohort studies have demonstrated that increased expression of CSF-1R is associated with ipsilateral breast cancer recurrence. Correlation with survival has not been reported. Our aim was to further evaluate the role of CSF-1R in breast cancer, by studying the expression of CSF-1R in a large cohort of clinical specimens.Experimental Design: Tissue microarrays containing 301 node-negative and 280 node-positive cases were used. Immunohistochemical staining was performed and correlated with overall survival, nodal status, and other clinicopathological data.Results: CSF-1R expression was strongly associated with nodal status. Of the node-negative cases, 114 (38.9%) stained positive for CSF-1R, whereas 189 (67.5%) of the node-positive cases expressed CSF-1R (P &lt; 0.0001). CSF-1R expression is also associated with larger tumor size (P = 0.02). Positive staining was strongly associated with decreased survival (P = 0.0003). Among node-negative patients, CSF-1R expression was associated with decreased overall survival (P = 0.045), whereas among node-positive patients, it was not (P = 0.47). In multivariate analysis, CSF-1R was not independent of nodal status as a predictor of survival.Conclusions: CSF-1R expression is a strong predictor of poor outcome in nonmetastatic breast cancer. It is significantly more frequently expressed in patients with nodal involvement. Among the node-negative patients, it has a stronger association with survival than among the node-positive patients. Our findings support other preclinical findings that CSF-1R may be involved in local invasion and metastasis. Thus, this receptor may be an effective target for therapeutic agents.
Effects of Acyclic Retinoid on Growth, Cell Cycle Control, Epidermal Growth Factor Receptor Signaling, and Gene Expression in Human Squamous Cell Carcinoma Cells
Authors: Shimizu Masahito , Suzui Masumi , Deguchi Atsuko , Lim Jin T. E. , Weinstein I. Bernard 
Published: September 2005

Abstract
We described recently the growth inhibitory effects of the novel compound acyclic retinoid (ACR) in human hepatoma cell lines (M. Suzui et al., Cancer Res., 62: 3997–4006, 2002). In this study we examined the cellular and molecular effects of ACR on human squamous cell carcinoma (SCC) cells. ACR inhibited growth of the esophageal SCC cell line HCE7, and the head and neck SCC cell lines YCU-N861 and YCU-H891, with IC50 values of ∼10, 25, and 40 μm, respectively. Detailed studies were then done with HCE7 cells. Treatment of these cells with 10 μm ACR caused an increase of cells in G0-G1 and induced apoptosis. This was associated with two phases of molecular events. During phase 1, which occurred within 6–12 h, there was an increase in the retinoic acid receptor β (RARβ) and p21CIP1 proteins, and their corresponding mRNAs, and a decrease in the hyperphosphorylated form of the retinoblastoma protein. During phase 2, which occurred at ∼24 h, there was a decrease in the cellular level of transforming growth factor α, and the phosphorylated (i.e., activated) forms of the epidermal growth factor receptor, Stat3, and extracellular signal-regulated kinase proteins, and a decrease in both cyclin D1 protein and mRNA. Reporter assays indicated that ACR inhibited the transcriptional activity of the cyclin D1, c-fos, and activator protein promoters. On the other hand, ACR markedly stimulated the activity of a retinoic acid response element-CAT reporter when the cells were cotransfected with a RARβ expression vector. A hypothetical model explaining these two phases is presented. The diverse effects that we obtained with ACR suggest that this agent might be useful in the chemoprevention and/or therapy of human SCCs.
Quantitative Analysis of Biomarkers Defines an Optimal Biological Dose for Recombinant Human Endostatin in Primary Human Tumors
Authors: Davis Darren W. , Shen Yu , Mullani Nizar A. , Wen Sijin , Herbst Roy S. , O’Reilly Michael , Abbruzzese James L. , McConkey David J. 
Published: September 2005

Abstract
Purpose: In a recent study, we presented preliminary evidence for biological activity in a Phase I dose-finding study (15–600 mg/m2) of recombinant human endostatin in patients with refractory solid tumors. Here, we conducted additional biomarker analyses to correlate changes in tumor biology with dose.
Experimental Design: Excisional tumor biopsies were obtained at baseline and after 56 days of endostatin therapy. Laser scanning cytometry (LSC) was used to quantify biomarker levels in whole tissue sections. Apoptosis in tumor cells (TCs) and tumor-associated endothelial cells (ECs) was quantified by fluorescent three-color anti-CD31/terminal deoxynucleotidyl transferase-mediated nick end labeling staining. Microvessel densities were measured by LSC-guided vessel contouring. Levels of tumor-associated EC BCL-2 and hypoxia-inducible factor 1α were determined by immunofluorescence and LSC quantification. The results, including tumor blood flow measured by positron emission tomography, were analyzed using a quadratic polynomial model.
Results: Significant increases in EC death and decreases in tumor microvessel density were observed, with maximal effects of endostatin at a dose of 249 mg/m2 (95% confidence interval, 159–338) and 257 mg/m2 (95% confidence interval, 183–331), respectively. In contrast, levels of TC death were uniformly low and did not correlate with endostatin dose. Maximal nuclear hypoxia-inducible factor 1α and minimal EC Bcl-2 levels were observed at ∼250 mg/m2, although the changes did not reach statistical significance.
Conclusions: The data suggest that endostatin had optimal biological activity at doses ∼250 mg/m2 in our cohort of patients. Endostatin’s failure to induce high levels of TC death may explain its lack of significant clinical activity in this Phase I trial.
Allelic Loss of a Common Microsatellite MarkerMYCL1
Authors: Kambara Takeshi , Sharp Gerald B. , Nagasaka Takeshi , Takeda Masanori , Sasamoto Hiromi , Nakagawa Hitoshi , Isozaki Hiroshi , MacPhee Donald G. , Jass Jeremy R. , Tanaka Noriaki , Matsubara Nagahide 
Published: September 2005

AbstractPurpose: Allelic loss involving chromosome arms 5q, 8p, 17p, and 18q is commonly detected in colorectal cancer (CRC). The short arm of chromosome 1 is also frequently affected in a whole range of cancer types, including CRC. Our aim in the present study was to determine whether allelic losses on 1p were likely to be of much value in predicting the prognosis of CRC cases.Experimental Design: Genomic DNA was prepared from tumor and corresponding normal tissue specimens from 90 patients who had undergone curative resection for CRC. Loss of heterozygosity (LOH) on chromosome arms 1p, 2p, 5q, 7q, 8p, 17p, 17q, and 18q was examined using 14 microsatellite markers, and possible correlations between LOH and clinicopathological factors (including tumor recurrence and patient survival) were investigated. LOH at the MYCL1 microsatellite marker at 1p34 was detected in 12 of 74 (16.2%) patients who were informative for this marker.Results: After controlling for tumor stage and gender and excluding findings for patients with remote metastasis, we found that patients who were positive for LOH at MYCL1 were 31 times more likely to experience recurrence than those who were negative for LOH at this locus (95% confidence intervals, 2.27-∞; P = 0.04). There were indications of a similar tendency for LOH at the 14-3-3-σ-TG microsatellite marker at 1p35, but we could find no evidence of a significant association between LOH at this site and tumor recurrence or patient survival. We were also unable to detect significant association between LOH at the various sites on 2p, 5q, 7q, 8p, 17p, 17q, and 18q and either tumor recurrence or patient survival.Conclusions: CRC patients whose tumors exhibited LOH at MYCL1 at chromosome 1p34 were likely to have a poor prognosis, suggesting that this marker may have clinical relevance.
Correlation of Major Cytogenetic Response with a Pharmacogenetic Marker in Chronic Myeloid Leukemia Patients Treated with Imatinib (STI571)
Authors: Dressman Marlene A. , Malinowski Rachel , McLean Lee Anne , Gathmann Insa , Capdeville Renaud , Hensley Martee ,   IRIS (International Randomized Study of Interferon-α versus STI571) Study Group, Polymeropoulos Mihael H. 
Published: September 2005

Abstract
Purpose: Imatinib, an inhibitor of the Bcr-Abl tyrosine kinase, is indicated for the treatment of patients with Philadelphia chromosome-positive chronic myeloid leukemia. We examined genotypes from patients enrolled in the International Randomized Study of IFN-α versus STI571 in an attempt to identify factors that associate with cytogenetic response.
Experimental Design: Sixty-eight polymorphic loci in 26 genes were examined in a subset of 187 patients (imatinib-treated patients, n = 113; IFN + 1-β-d-arabinofuranosylcytosine-treated patients, n = 74). Correlations between genotype and major cytogenetic response (MCyR) were examined by Fisher’s exact tests. Multivariate and survival analyses were also performed.
Results: A significant association between MCyR and the rs2290573 polymorphism mapped to 15q22.33 was observed in imatinib-treated patients (P = 0.00037, Bonferroni corrected P = 0.025). Individuals with a CC genotype at this locus had a MCyR rate of 52% compared with individuals with a CT or TT genotype that had a MCyR rate of 89% (odds ratio, 6.72; 95% confidence interval, 1.51–29.91). In a multivariate analysis, the rs2290573 polymorphism was significant, whereas Sokal score was not. Time to progression analysis illustrated a significant difference based on genotype for the rs2290573 polymorphism.
Conclusions: A significant association was identified between the genetic polymorphism rs2290573 and MCyR in imatinib-treated patients. This polymorphism is located in the intronic sequence of a putative gene with a tyrosine kinase domain. Multivariate analysis suggests that an individual’s genotype for rs2290573 has more predictive value for MCyR than prognostic variables such as Sokal score. The clinical relevance of these results requires validation in future clinical trials.
Age-Dependent Prognostic Effects of Genetic Alterations in Glioblastoma
Authors: Batchelor Tracy T. , Betensky Rebecca A. , Esposito J. Matthew , Pham Loc-Duyen D. , Dorfman Molly V. , Piscatelli Nicole , Jhung Sarah , Rhee David , Louis David N. 
Published: September 2005

Abstract
Purpose: Although the genetic alterations in glioblastoma have been well characterized, reports regarding their prognostic effects have been inconsistent.
Experimental Design: In this series of 140 consecutive cases of glioblastoma treated at a single center, we analyzed the frequency, age dependency and prognostic effects of TP53 mutation, CDKN2A/p16 deletion, EGFR amplification, as well as loss of chromosome 1p, chromosome 10q, and chromosome 19q. The complete set of genetic alterations was available on 60 of 140 patients.
Results: In this cohort of glioblastoma cases, TP53 mutation was significantly associated with patient age. The prognostic effects of TP53 mutation, EGFR amplification, CDKN2A/p16 alterations, and loss of chromosome 1p were dependent on the age of the patient.
Conclusions: This is the first observation that the prognostic effects of TP53, 1p, and CDKN2A/p16 alterations are dependent on patient age. These observations concerning the interactions of age and genetic changes in glioblastoma suggest that tumorigenic pathways to glioblastoma vary with the age of the patient and that future molecular marker studies should carefully evaluate the potential age-dependent prognostic effects of these biological variables. The inconsistent or negative prognostic effects of molecular markers reported in prior studies of glioblastoma may be because different effects at different ages may have resulted in a cancellation of an overall effect in the entire cohort.
Molecular Serological Detection of DNA Alterations in Transitional Cell Carcinoma Is Highly Sensitive and Stage Independent
Authors: von Knobloch Rolf , Brandt Heidrun , Schrader Andres J. , Heidenreich Axel , Hofmann Rainer 
Published: September 2005

AbstractPurpose: To evaluate the efficacy of fluorescent microsatellite analysis (MSA) for the serological diagnosis of transitional cell carcinoma (TCC) of the urinary tract analyzing free tumor DNA in the serum of cancer patients.Experimental Design: We applied fluorescent MSA to detect serum–DNA alterations in patients suffering from bladder and upper urinary tract TCC and prospectively collected fresh tumor, peripheral blood, and serum specimens from 61 consecutive patients to obtain the corresponding DNA. Fluorescent MSA was performed with a total of 17 polymorphic markers from the chromosomal regions 5q, 8p, 9p, 9q, 13q, 14q, 17p, 17q, and 20q in the 61 cancer patients, as well as in 20 healthy controls.Results: Molecular serological analysis led to tumor-specific diagnosis of TCC in 80.3% (49 of 61) of cases. Four healthy controls displayed serum–DNA artifacts rendering a specificity of 80%. The highest frequency of serum–DNA alterations was detected for chromosomal region 8p with 36%. Chromosomes 5q, 9p, and 20q showed serum–DNA alterations in 18 to 21%. The identification of serum–DNA alterations was not statistically associated with underlying local tumor stage (P = 0.29) but was more frequent in high-grade tumors (P = 0.08).Conclusions: MSA offers a highly sensitive method for serological diagnosis of TCC. To optimize specificity, simultaneous analysis of tumor DNA is advised to rule out artifacts resembling allelic imbalance in MSA of serum DNA.
MIB-1 (KI-67) Proliferation Index and Cyclin-Dependent Kinase Inhibitor p27Kip1 Protein Expression in Nephroblastoma
Authors: Ghanem Mazen A. , Van der Kwast Theo H. , Sudaryo Mondastri K. , Mathoera Rejiv B. , van den Heuvel Marry M. , Al-Doray Abdel-Alim M. , Nijman Rien M. , van Steenbrugge Gert J. 
Published: September 2005

Abstract
Purpose: A number of studies have indicated that the tumor proliferation marker MIB-1 and cell cycle inhibitor p27Kip1 expression are of prognostic importance in a variety of cancers. The present study was performed to evaluate the prognostic value of these molecules in Wilms’ tumors.
Experimental Design: MIB-1 and p27Kip1 expressions were investigated by the means of immunohistochemical analysis of 62 Wilms’ tumor. Patients were preoperatively treated by chemotherapeutic agents and had a mean follow-up of 5.7 years.
Results: MIB-1 and p27Kip1 were expressed in normal kidney tissues and in the three main components of Wilms’ tumor, i.e., the blastemal, epithelial, and stromal cells. In Wilms’ tumors, the percentage of MIB-1-positive cells in the blastema ranged between 0 and 42% (mean, 9.4%) and in the epithelial component between 0 and 53% (mean, 19.9%), with a significant difference (P &lt; 0.01). The percentage of blastemal p27Kip1-positive cells ranged between 3 and 85% (mean, 55.1%) and for the epithelial component between 1 and 87% (mean, 59%). There was a significant inverse relationship between blastemal MIB-1 and p27Kip1 expression in Wilms’ tumor. Univariate analysis showed that blastemal MIB-1 and p27Kip1 expression were indicative for clinical progression and tumor-specific survival. In a multivariate analysis, blastemal MIB-1 and p27Kip1 protein expression proved to be an independent prognostic for clinical progression besides stage.
Conclusions: It was concluded that both MIB-1-based proliferative activity and p27Kip1 protein expression in the blastema have prognostic impact in Wilms’ tumor.
Abrogation of p21 Expression by Flavopiridol Enhances Depsipeptide-Mediated Apoptosis in Malignant Pleural Mesothelioma Cells
Authors: Nguyen Dao M. , Schrump William D. , Chen G. Aaron , Tsai Wilson , Nguyen Phuongmai , Trepel Jane B. , Schrump David S. 
Published: September 2005

Abstract
Purpose: Recent insights regarding the pathogenesis of malignant pleural mesothelioma (MPM) provide new opportunities for targeted molecular therapies for this highly lethal disease. The present study was undertaken to examine the effects of the histone deacetylase inhibitor, Depsipeptide (DP) FK228, in conjunction with the cyclin-dependent kinase inhibitor, Flavopiridol (FLA), in cultured MPM cells.
Experimental Design: Proliferation and apoptosis in drug-treated, virally transduced, or control cells were assessed by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide and Apo-bromodeoxyuridine techniques. Western blot and ELISA techniques were used to examine signal transduction and cell cycle-related protein levels in MPM cells exposed to DP and/or FLA in the presence or absence of calphostin, phorbol-12,13-dibutyrate, 5,6-dichloro-1-β-d-ribofuranosyl-benzimidazole, or adenoviral p21 transduction.
Results: DP (1–50 ng/ml × 6 h) or FLA (100–200 nm × 72 h) alone, mediated low-level, dose-dependent growth inhibition in MPM cells. In contrast, sequential DP/FLA treatment mediated marked growth inhibition and apoptosis in these cell lines. The cytotoxic effects of DP/FLA were considerably less pronounced in cultured normal cells. The proapoptotic effects of DP/FLA treatment coincided with inhibition of DP-mediated induction of p21 by FLA. Overexpression of p21 by adenoviral gene transfer techniques rendered MPM cells refractory to the cytotoxic effects of this treatment regimen. In p21 reporter assays, promoter activation by DP was antagonized by FLA. The magnitude of inhibition of DP-mediated p21 induction by FLA exceeded that observed with the pTEFb antagonist 5,6-dichloro-1-β-d-ribofuranosyl-benzimidazole. Calphostin C abrogated p21 induction mediated by DP and enhanced DP-mediated apoptosis in a manner comparable with FLA in MPM cells; in contrast, phorbol-12,13-dibutyrate blocked FLA-mediated inhibition of p21 induction by DP and markedly protected these cells from the apoptotic effects of sequential DP/FLA.
Conclusions: FLA abrogates DP-mediated induction of p21 expression, in part, via inhibition of protein kinase C signaling and markedly potentiates the cytotoxic effects of DP in MPM cells.
Osteoblast-Derived Factors Induce Androgen-Independent Proliferation and Expression of Prostate-Specific Antigen in Human Prostate Cancer Cells
Authors: Blaszczyk Natalie , Masri Bassam A. , Mawji Nasrin R. , Ueda Takeshi , McAlinden Gavan , Duncan Clive P. , Bruchovsky Nicholas , Schweikert Hans-Udo , Schnabel Doris , Jones Edward C. , Sadar Marianne D. 
Published: September 2005

Abstract
Purpose: Prostate cancer metastasizes to the skeleton to form osteoblastic lesions. Androgen ablation is the current treatment for metastatic prostate cancer. This therapy is palliative, and the disease will return in an androgen-independent form that is preceded by a rising titer of prostate-specific antigen (PSA). Here, we investigated the possibility that human osteoblasts might secrete factors that contribute to the emergence of androgen-independent prostate cancer.
Experimental Design: Primary cultures of human osteoblasts were used as a source of conditioned medium (OCM). Proliferation, expression of androgen-regulated genes, and transactivation of the androgen receptor (AR) were monitored in LNCaP human prostate cancer cells in response to OCM using the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay, Northern blot analysis, and reporter gene constructs. Levels of interleukin-6 (IL-6) present in OCM were measured, and its contribution to proliferation and expression of PSA were investigated by neutralization studies with anti IL-6 antibodies.
Results: OCM increased the proliferation and expression of PSA at both the protein and RNA levels in LNCaP cells. Synergistic increases in the activities of PSA (6.1 kb)- and pARR3-tk-luciferase reporters were measured in cells cotreated with both OCM and androgen. OCM targeted the NH2-terminal domain of the AR. The effect of OCM on transcriptional activity of the AR was inhibited by an antiandrogen. Neutralizing antibodies to IL-6 blocked proliferation and expression of PSA by OCM.
Conclusion: Osteoblasts secrete factors, such as IL-6, that cause androgen-independent induction of PSA gene expression and proliferation of prostate cancer cells by a mechanism that partially relies on the AR. Identifying such molecular mechanisms may lead to improved clinical management of metastatic prostate cancer.