bluuebunny/crossref_metadata_2025_split huggingface dataset:
Prognostic Significance of Transforming Growth Factor β Receptor II in Estrogen Receptor-Negative Breast Cancer Patients
Authors: Buck Miriam B. , Fritz Peter , Dippon Juergen , Zugmaier Gerhard , Knabbe Cornelius 
Published: September 2005

Abstract
Purpose: The role of transforming growth factor β (TGF-β) in breast cancer is ambiguous; it can display both tumor suppressing and enhancing effects. Activation of the TGF-β signal transduction system is subject to hormonal regulation. This study was conducted to further analyze the role of TGF-β receptors in breast cancer and to evaluate their significance as prognostic markers.
Experimental Design: Expression of TGF-β receptor I (TβRI) and TGFβ receptor II (TβRII) was retrospectively analyzed by immunohistochemistry in 246 breast cancer patients.
Results: Expression of TβRI was strongly correlated with tumor size (P &lt; 0.001) and nodal status (P = 0.012) but only weakly with overall survival (P = 0.056). In contrast, TβRII was prognostic for overall survival in univariate analysis (P = 0.0370). In estrogen receptor (ER) -negative patients TβRII expression was correlated with highly reduced overall survival (P = 0.0083). In multivariate analysis TβRII proved to be an independent and highly significant prognostic marker with a hazard ratio of 6.8. Simultaneous loss of both ER and TβRII was associated with longer overall survival times comparable with those of ER-positive patients.
Conclusions: The results of this exploratory study show that TβRII is an independent, highly significant prognostic indicator for overall survival in ER-negative patients. In addition our results are supportive of a mechanism of breast cancer progression in which a selective loss of the tumor inhibitory action of TGFβ takes place, whereas tumor- promoting aspects remain intact.
Use of Replicating Oncolytic Adenoviruses in Combination Therapy for Cancer
Authors: Chu Roland L. , Post Dawn E. , Khuri Fadlo R. , Van Meir Erwin G. 
Published: September 2005

Abstract
Oncolytic virotherapy is the use of genetically engineered viruses that specifically target and destroy tumor cells via their cytolytic replication cycle. Viral-mediated tumor destruction is propagated through infection of nearby tumor cells by the newly released progeny. Each cycle should amplify the number of oncolytic viruses available for infection. Our understanding of the life cycles of cytolytic viruses has allowed manipulation of their genome to selectively kill tumor cells over normal tissue. Because the mechanism of tumor destruction is different, oncolytic virotherapy should work synergistically with current modes of treatment such as chemotherapy and radiation therapy. This article focuses on oncolytic adenoviruses that have been created and tested in preclinical and clinical trials in combination with chemotherapy, radiation therapy, and gene therapy.
Multiple Myeloma Regression Mediated by Bruceantin
Authors: Cuendet Muriel , Christov Konstantin , Lantvit Daniel D. , Deng Yunfan , Hedayat Samad , Helson Lawrence , McChesney James D. , Pezzuto John M. 
Published: September 2005

Abstract
Purpose: Bruceantin has been shown to induce cell differentiation in a number of leukemia and lymphoma cell lines. It also down-regulated c-MYC, suggesting a correlation of down-regulation with induction of cell differentiation or cell death. In the present study, we focused on multiple myeloma, using the RPMI 8226 cell line as a model.
Experimental Design: The effects of bruceantin on c-MYC levels and apoptosis were examined by immunoblotting, 4′,6-diamidino-2-phenylindole staining, evaluation of caspase-like activity, and 3,3′-dihexyloxacarbocyanine iodide staining. The potential of bruceantin to inhibit primary tumor growth was assessed with RPMI 8226 xenografts in SCID mice, and apoptosis in the tumors was evaluated by the terminal deoxynucleotidyl transferase-mediated nick end labeling assay.
Results: c-MYC was strongly down-regulated in cultured RPMI 8226 cells by treatment with bruceantin for 24 h. With U266 and H929 cells, bruceantin did not regulate c-MYC in this manner. Apoptosis was induced in the three cell lines. In RPMI 8226 cells, apoptosis occurred through proteolytic processing of procaspases and degradation of poly(ADP-ribose) polymerase. The mitochondrial pathway was also involved. Because RPMI 8226 cells were the most sensitive, they were used in a xenograft model. Bruceantin treatment (2.5–5 mg/kg) resulted in a significant regression of tumors without overt toxicity. Apoptosis was significantly elevated in tumors derived from animals treated with bruceantin (37%) as compared with the control tumors (14%).
Conclusions: Bruceantin interferes with the growth of RPMI 8226 cells in cell culture and xenograft models. These results suggest that bruceantin should be reinvestigated for clinical efficacy against multiple myeloma and other hematological malignancies.
Synchronous Overexpression of Epidermal Growth Factor Receptor and HER2-
neu
Protein Is a Predictor of Poor Outcome in Patients with Stage I Non-Small Cell Lung Cancer
Authors: Onn Amir , Correa Arlene M. , Gilcrease Michael , Isobe Takeshi , Massarelli Erminia , Bucana Corazon D. , O’Reilly Michael S. , Hong Waun K. , Fidler Isaiah J. , Putnam Joe B. , Herbst Roy S. 
Published: September 2005

Abstract
Purpose: Despite maximal therapy, surgically treated patients with stage I non-small cell lung cancer (NSCLC) are at risk for developing metastatic disease. Histopathologic findings cannot adequately predict disease progression, so there is a need to identify molecular factors that serve this purpose. Because the ErbB receptors play an important role in lung cancer progression, we analyzed the expression of epidermal growth factor receptor (EGFR), phosphorylated EGFR, transforming growth factor α (TGFα), and HER2-neu as potential prognostic factors in stage I NSCLC.
Experimental Design: Using immunohistochemical techniques, we retrospectively analyzed formalin-fixed, paraffin-embedded samples from 111 patients with resected pathological stage I NSCLC. Then we correlated these data with patient clinical outcome.
Results: Median follow-up was 69.3 months. EGFR overexpression (defined as &gt;10% membranous staining) was found in 66 tumors (59.5%). It was significantly more common in T2 tumors than in T1 tumors (P = 0.001), and in more squamous cell carcinomas than in adenocarcinomas (P = 0.07). HER2-neu overexpression was found in 19 tumors (17.1%) and was significantly more common in adenocarcinomas than in squamous cell carcinomas (P = 0.035). Synchronous overexpression of EGFR and HER2-neu was found in 11 tumors (9.9%). Patients with these tumors had a significantly shorter time to recurrence (P = 0.006) and a trend toward shorter overall survival (P = 0.093). Phosphorylated EGFR and transforming growth factor α were detected but were not related to prognosis.
Conclusions: Synchronous overexpression of EGFR and HER2-neu at the protein level predicts increased recurrence risk and may predict decreased survival in patients with stage I NSCLC. This suggests that important interactions take place among the different members of the ErbB family during tumor development and suggests a method for choosing targeted therapy. A prospective study is planned.
The 5A/6A Polymorphism of the Matrix Metalloproteinase 3 Gene Promoter and Breast Cancer
Authors: Krippl Peter , Langsenlehner Uwe , Renner Wilfried , Yazdani-Biuki Babak , Köppel Herwig , Leithner Andreas , Wascher Thomas C. , Paulweber Bernhard , Samonigg Hellmut 
Published: September 2005

Abstract
Purpose: The matrix metalloproteinase 3 (MMP3), also known as stromelysin-I, is a key-player for carcinogenesis and tumor growth. A 5A/6A promoter polymorphism is associated with differences in MMP3 activity and has been linked to cancer susceptibility in some studies. In the present study we evaluated the role of this polymorphism for breast cancer risk.
Experimental Design: A case–control study was performed including 500 patients with histologically confirmed breast cancer and 500 female, age-matched, healthy control subjects from population-based screening studies. The MMP3 5A/6A polymorphism was determined by a 5′-nuclease (TaqMan) assay.
Results: Prevalences of 5A/5A, 5A/6A, and 6A/6A genotypes were similar among patients (20.6, 51.8, and 27.6%, respectively) and controls (23.3, 47.3, and 29.4%, P = 0.34). The odds ratio of carriers of a MMP3 5A allele for breast cancer was 1.09 (95% confidence interval, 0.83–1.44). Patients with the 5A/5A genotype had a higher proportion of lymph-node metastases than those with a 5A/6A or 6A/6A genotype (P = 0.010).
Conclusions: The MMP3 5A/6A promoter polymorphism does not appear to influence breast cancer susceptibility but may be linked to a higher risk for metastasizing among breast cancer patients.
CpG Immunostimulatory Oligodeoxynucleotide 1826 Enhances Antitumor Effect of Interleukin 12 Gene-Modified Tumor Vaccine in a Melanoma Model in Mice
Authors: Switaj Tomasz , Jalili Ahmad , Jakubowska Anna B. , Drela Nadzieja , Stoksik Magdalena , Nowis Dominika , Basak Grzegorz , Golab Jakub , Wysocki Piotr J. , Mackiewicz Andrzej , Sasor Agata , Socha Koryna , Jakóbisiak Marek , Lasek Witold 
Published: September 2005

Abstract
Purpose: The effectiveness of interleukin (IL)-12-secreting tumor vaccines in the treatment of mouse tumors could be enhanced by concurrent application of cytokines and costimulatory molecules. We investigated the therapeutic potential of IL-12 gene-transduced melanoma vaccine in combination with CpG immunostimulatory oligodeoxynucleotide (ODN) 1826, an adjuvant known to favor development of Th1-biased immune response, in a B78-H1 (B78) melanoma model in mice.
Experimental Design: Mice injected with B78 melanoma cells were treated with irradiated IL-12 gene-transduced B78 cells [B78/IL-12(X)] and/or ODN 1826. Mechanisms responsible for the antitumor effects of the treatment were investigated using fluorescence-activated cell sorter analysis, a standard 51Cr releasing assay, 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay, and ELISA.
Results: Single injection of B78/IL-12(X) cells had no effect on tumor growth, whereas seven consecutive daily injections of ODN 1826 markedly inhibited tumor progression with occasional curative effects. When used in combination, B78/IL-12(X) cells and ODN 1826 caused additional tumor growth reduction and eradication of tumors in 62% of treated mice. The combined treatment activated local inflammatory response against tumor but also induced systemic antitumor immunity. In vitro studies have shown that when used together, B78/IL-12(X) cells and ODN 1826 induced a potent Th1 response and suggested the role of IFN-γ in activation of the host immune response. The antitumor effects in double-treated mice were accompanied by the development of cytotoxic effectors in the spleen and activation of macrophages.
Conclusions: The results provided the evidence that the combination of IL-12 gene-modified melanoma vaccine and ODN 1826 induces synergistically systemic and local antitumor immunity.
Different Genetic Features Associated with Colon and Rectal Carcinogenesis
Authors: Frattini Milo , Balestra Debora , Suardi Simona , Oggionni Maria , Alberici Paola , Radice Paolo , Costa Aurora , Daidone Maria Grazia , Leo Ermanno , Pilotti Silvana , Bertario Lucio , Pierotti Marco A. 
Published: September 2005

AbstractPurpose: The issue of whether colon and rectal cancer should be considered as a single entity or two distinct entities is still debated, and there is a need to improve studies addressing the heterogeneity of the pathogenetic pathway leading to sporadic colorectal cancers (SCRCs) as well as to identify biological and/or molecular differences between colon and rectal cancers.Experimental Design: Specimens of SCRCs were analyzed for somatic mutations in APC, K-ras, and TP53 genes and loss-of-heterozygosity of chromosome 18.Results: Eleven SCRCs showed microsatellite instability. APC mutation frequency was significantly lower in microsatellite instability (MIN+) than in MIN− SCRCs. All MIN− SCRCs showed β-catenin overexpression. A combined analysis of the biomarkers revealed two pathways mainly represented by MIN− SCRCs and differently followed on the basis of tumor location, APC-K-ras-TP53-Ch18q and APC-TP53-Ch18q.Conclusions: The APC-β-catenin pathway is inactivated in MIN− SCRCs and represents the first hit of SCRC development. Two preferential pathways followed by SCRCs occur, one K-ras dependent, in agreement with the Fearon and Vogelstein model, and the other K-ras independent. Significant differences between colon and rectal tumors occur in our series of MIN− SCRCs. The different pathways observed and their distribution can be summarized as follows: (a) K-ras mutations were more commonly detected in colon than in rectum; (b) the number of mutations detected was significantly higher in colon than in rectal tumors; and (c) a mutational pattern restricted to the APC gene was more common in rectal than in colon tumors. This molecular characterization can be translated into a clinical setting to improve diagnosis and to direct a rationale pharmacological treatment.
Evaluation of the Therapeutic Potential of the Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitor Gefitinib in Preclinical Models of Bladder Cancer
Authors: Dominguez-Escrig Jose L. , Kelly John D. , Neal David E. , King Sonya M. , Davies Barry R. 
Published: September 2005

Abstract
The epidermal growth factor receptor (EGFR) is associated with aggressive phenotypes and is an independent predictor of stage progression and mortality in bladder cancer. Gefitinib (‘Iressa,’ ZD1839) is an orally active EGFR-tyrosine kinase inhibitor. The objective of this study was to evaluate the in vitro and in vivo effects of gefitinib in the EGFR-expressing human bladder cancer cell lines 253J B-V, RT-112, and T24. EGFR expression was 3- and 2-fold higher in 253J B-V and RT-112, respectively, compared with T24 cells. Ten μm gefitinib inhibited EGFR, p42/44 extracellular signal-regulated kinase (ERK), and Akt/protein kinase B phosphorylation in all three of the cell lines. Inhibition of ERK by gefitinib was significantly greater in 253J B-V compared with RT-112 and T24 cells (9:2:1 in 253J B-V:RT-112:T24), whereas inhibition of Akt phosphorylation was less in 253J B-V compared with RT-112 and T24 cells (1:9:30 in 253J B-V:RT-112:T24). When cultured in serum-free medium supplemented with epidermal growth factor, 10 μm gefitinib inhibited DNA synthesis in T24 and RT-112 cells, whereas 1 μm gefitinib was sufficient to inhibit DNA synthesis in 253J B-V cells. Similarly, in the presence of serum, 10 μm gefitinib induced a significant reduction in S-phase and viable cell number in T24 and RT-112 cells, whereas 1–10 μm gefitinib caused a dose-dependent effect on these phenotypes in 253J B-V cells. Gefitinib significantly enhanced the ability of ionizing radiation to reduce colony forming ability in 253J B-V and RT-112 cells. In nude mice, a daily oral dose of 150 mg/kg gefitinib induced regression of tumors produced by 253J B-V cells growing at s.c. sites and suppression of tumors produced by these cells at orthotopic sites but had no effect on tumors produced by RT-112 cells growing at s.c. sites. The data indicates that gefitinib has potential therapeutic value, alone or in combination with ionizing radiation, in a subset of EGFR-expressing bladder cancers. However, there is a differential response to gefitinib in these EGFR-expressing bladder cancer cell lines. Although gefitinib can inhibit phosphorylation of EGFR, ERK, and Akt, and inhibit growth of bladder cancer cells in vitro, it does not necessarily inhibit growth of bladder cancer cells in vivo. It is likely that optimized therapy approaches will require an accurate “molecular” diagnosis allowing effective, selective, tailored therapeutic strategies to be designed.
Bioactive Suture
Authors: Shibuya Terry Y. , Kim Sanghun , Nguyen Kevin , Do Johnny , McLaren Christine E. , Li Kuo-Tung , Chen Wen-Pin , Parikh Parag , Wadhwa Ashish , Zi Xiaolin , Chen Vincent Y. , Wong Hau-Sin , Armstrong William B. , Yoo George H. 
Published: September 2005

AbstractPurpose: We have proposed to characterize the mechanism through which bioactive surgical sutures generate a TH1 immune response and to define the immune-stimulating half-life of the sutures.Experimental Design: Bioactive sutures of interferon γ (IFNγ), interleukin 2 (IL-2), anti-CD3/CD28, anti-CD3/CD28 + IL-2, or anti-CD3/CD28 + IFNγ sutures were used to stimulate lymphocytes from normal donors and from head and neck cancer patients in vitro over a 24-day period. Cell supernatants were analyzed by ELISA, and T cells were phenotyped to characterize the immune response generated. Intracellular cytokine staining was performed to measure the expansion of flu-specific T cells. Electromobility shift assay and supershift assay were used to measure the intranuclear DNA binding activity of nuclear factor κB and its p65 subunit in T cells activated by sutures in the presence and absence of a proteasome inhibitor, MG-132.Results: Anti-CD3/CD28, anti-CD3/CD28 + IL-2, or anti-CD3/CD28 + IFNγ generated a prolonged TH1 immune response for 18 days in vitro. Anti-CD3/CD28 expanded flu-specific T cells. Activated T cells demonstrated enhanced CD40 ligand (CD40L) expression within 72 hours of stimulation, which stimulated other cells to secrete IL-12. Stimulated T cells demonstrated increased intranuclear expression of nuclear factor-κB, which was blocked by MG-132, and also reduced CD40L and IL-12 expression.Conclusions: This is the first report to demonstrate that bioactive surgical sutures can generate a prolonged TH1 immune response and expand flu-specific T cells. Bioactive sutures, which are primarily a T-cell stimulant, also stimulated other cells to secrete IL-12 and prolonged the immune response. Sutures may provide a novel in situ stimulating strategy for enhancing the immune system of cancer patients.
Her2/neu Expression Predicts the Response to Antiaromatase Neoadjuvant Therapy in Primary Breast Cancer
Authors: Zhu Li , Chow Louis W. C. , Loo Wings T. Y. , Guan Xin-Yuan , Toi Mazakazu 
Published: September 2005

Abstract
Purpose: Many studies suggest that Her2/neu play an important role in neoadjuvant endocrine therapy. This study aimed to determine whether the level of Her2/neu expression in advanced breast cancer changes after antiaromatase neoadjuvant treatment, as well as to identify the relationship between Her2/neu expression and response to this kind of therapy.
Experimental Design: Thirty-six postmenopausal patients with hormonal receptor-positive primary breast cancer were included in a study of three monthly cycles of neoadjuvant endocrine therapy with either Aromasin (25 mg daily) or Femara (2.5 mg daily). Immunohistochemistry (IHC) and fluorescence in situ hybridization (FISH) for Her2/neu were conducted both on pretreatment biopsies and surgical tumors.
Results: Using IHC, 5 of 36 (13.9%) of the patients had a Her2/neu overexpression after treatment, as compared with 16 of 36 (44.4%) before. Meanwhile, there was no change in 21 (58.3%) patients, and through FISH, there was a change from amplification to no amplification in 15 (41.7%) patients. The response rate to the treatment was 75% for Her2/neu (+) tumors and 35% for Her2/neu (−) tumors (P = 0.017) while FISH was performed. The response rate was also significantly affected by the decrease in Her2/neu status after the treatment, with 73% of the tumors showing decreased Her2/neu expression and with 38% of the tumors showing no change of Her2/neu expression (P = 0.037).
Conclusions: Using both IHC and FISH, advanced breast cancers show statistical evidence of decreasing incidence of Her2/neu expression after antiaromatase neoadjuvant treatment. Our data also suggest that Her2/neu expression and its change during the treatment might be predictive markers for this kind of therapy.
Depleted Dopamine in Gastric Cancer Tissues
Authors: Chakroborty Debanjan , Sarkar Chandrani , Mitra Rita Basu , Banerjee Samir , Dasgupta Partha Sarathi , Basu Sujit 
Published: September 2005

Abstract
Purpose: It has been recently shown that the catecholamine neurotransmitter dopamine (DA) strongly and selectively inhibits vascular permeability factor/vascular endothelial growth factor (VPF/VEGF)-induced angiogenesis. Gastric cancer is highly angiogenic and is dependent on VEGF for its growth and progression. Because substantial amounts of DA present in normal stomach tissues has been implicated in several gastric functions, we therefore investigated the role, if any, of this neurotransmitter in the growth and progression of gastric cancer.
Experimental Design: Initially, the status of DA and tyrosine hydroxylase, the rate-limiting enzyme required for DA synthesis, were determined in human gastric cancer tissues and in N-methyl-N′-nitro-N-nitrosoguanidine (MNNG)-induced gastric cancer tissues of rats. On the basis of our observation of inverse correlation between stomach DA and gastric cancer growth, we determined the effect of pharmacological dose of DA on the angiogenesis and growth of MNNG induced gastric cancer in rats and Hs746T human gastric cancer in nude mice.
Results: DA and tyrosine hydroxylase were absent in both human and rat gastric cancer tissues. On the contrary, a low nontoxic pharmacological dose of DA significantly retarded tumor angiogenesis by inhibiting VEGFR-2 phosphorylation in tumor endothelial cells, which expressed DA D2 receptors. This action of DA was associated with the growth inhibition of both MNNG-induced rat malignant gastric tumors and xenotransplanted human gastric cancer in nude mice.
Conclusions: Our study demonstrates that there is an inverse correlation between endogenous stomach DA and gastric cancer and indicates that DA already in clinical use for other purposes might have a role as an antiangiogenic agent in the treatment of gastric cancer.
Overexpression of the Cell Adhesion Molecules DDR1, Claudin 3, and Ep-CAM in Metaplastic Ovarian Epithelium and Ovarian Cancer
Authors: Heinzelmann-Schwarz Viola A. , Gardiner-Garden Margaret , Henshall Susan M. , Scurry James , Scolyer Richard A. , Davies Michael J. , Heinzelmann Matthias , Kalish Larry H. , Bali Anish , Kench James G. , Edwards Lyndal S. , Bergh Patricia M. Vanden , Hacker Neville F. , Sutherland Robert L. , O’Brien Philippa M. 
Published: September 2005

Abstract
Purpose: A better understanding of the molecular pathways underlying the development of epithelial ovarian cancer (EOC) is critical to identify ovarian tumor markers for use in diagnostic or therapeutic applications. The aims of this study were to integrate the results from 14 transcript profiling studies of EOC to identify novel biomarkers and to examine their expression in early and late stages of the disease.
Experimental Design: A database incorporating genes identified as being highly up-regulated in each study was constructed. Candidate tumor markers were selected from genes that overlapped between studies and by evidence of surface membrane or secreted expression. The expression patterns of three integral membrane proteins, discoidin domain receptor 1 (DDR1), claudin 3 (CLDN3), and epithelial cell adhesion molecule, all of which are involved in cell adhesion, were evaluated in a cohort of 158 primary EOC using immunohistochemistry.
Results: We confirmed that these genes are highly overexpressed in all histological subtypes of EOC compared with normal ovarian surface epithelium, identifying DDR1 and CLDN3 as new biomarkers of EOC. Furthermore, we determined that these genes are also expressed in ovarian epithelial inclusion cysts, a site of metaplastic changes within the normal ovary, in borderline tumors and in low-grade and stage cancer. A trend toward an association between low CLDN3 expression and poor patient outcome was also observed.
Conclusions: These results suggest that up-regulation of DDR1, CLDN3, and epithelial cell adhesion molecule are early events in the development of EOC and have potential application in the early detection of disease.