bluuebunny/crossref_metadata_2025_split huggingface dataset:
Dual Inhibition of Epidermal Growth Factor Receptor and Vascular Endothelial Growth Factor Receptor Phosphorylation by AEE788 Reduces Growth and Metastasis of Human Colon Carcinoma in an Orthotopic Nude Mouse Model
Authors: Yokoi Kenji , Thaker Premal H. , Yazici Sertac , Rebhun Robert R. , Nam Do-Hyun , He Junqin , Kim Sun-Jin , Abbruzzese James L. , Hamilton Stanley R. , Fidler Isaiah J. 
Published: September 2005

Abstract
We studied growth factors and their receptors in tumor cells and tumor-associated endothelial cells as the therapeutic targets in colon cancer. Immunohistochemical analysis of 13 surgical specimens of human colon adenocarcinoma revealed that both tumor cells and tumor-associated endothelial cells in 11 of the 13 specimens expressed the epidermal growth factor (EGF), transforming growth factor α (TGF-α), EGF receptor (EGFR), phosphorylated EGFR (pEGFR), vascular endothelial growth factor (VEGF), VEGF receptor (VEGFR), and phosphorylated VEGFR (pVEGFR). HT29 human colon cancer cells growing orthotopically in the cecum of nude mice expressed a high level of EGF, EGFR, pEGFR, VEGF, VEGFR, and pVEGFR. Double-immunofluorescence staining found that tumor-associated mouse endothelial cells also expressed pEGFR and pVEGFR. Tumors in mice treated for 5 weeks with oral AEE788 (an inhibitor of EGFR and VEGFR tyrosine kinase) as a single agent or with CPT-11 alone were smaller (&gt;50%) than those in control mice. Mice treated with the combination of AEE788 and CPT-11 had significantly smaller tumors (P &lt; 0.01) and complete inhibition of lymph node metastasis. AEE788 alone or in combination with CPT-11 inhibited pEGFR, pVEGFR, and phosphorylated Akt expression on tumor-associated endothelial cells as well as on tumor cells. The combination therapy also significantly decreased microvessel density and tumor cell proliferation and increased the level of apoptosis in both tumor cells and tumor-associated endothelial cells. Collectively, these data suggest that the dual inhibition of EGFR and VEGFR signaling pathways in tumor cells and tumor-associated endothelial cells in combination with chemotherapy can provide a new approach to the treatment of colon cancer.
Bortezomib Abolishes Tumor Necrosis Factor–Related Apoptosis-Inducing Ligand Resistance via a p21-Dependent Mechanism in Human Bladder and Prostate Cancer Cells
Authors: Lashinger Laura M. , Zhu Keyi , Williams Simon A. , Shrader Marissa , Dinney Colin P.N. , McConkey David J. 
Published: September 2005

Abstract
Tumor necrosis factor–related apoptosis-inducing ligand (TRAIL) is a member of the tumor necrosis factor family of cytokines that induces apoptosis in some tumor cells but not in normal cells. Unfortunately, many human cancer cell lines are refractory to TRAIL-induced cell death, and the molecular mechanisms underlying resistance are unclear. Here we report that TRAIL resistance was reversed in human bladder and prostate cancer cell lines by the proteasome inhibitor bortezomib (PS-341, Velcade). Synergistic induction of apoptosis occurred within 4 to 6 hours in cells treated with TRAIL plus bortezomib and was associated with accumulation of p21WAF-1/Cip-1 (p21) and inhibition of cyclin-dependent kinase (cdk) activity. Roscovitine, a specific cdk1/2 inhibitor, also sensitized cells to TRAIL. Silencing p21 expression reduced levels of DNA fragmentation by 50% in cells treated with bortezomib and TRAIL, confirming that p21 was required for the response. Analysis of the TRAIL pathway revealed that caspase-8 processing was enhanced in a p21-dependent fashion in cells exposed to TRAIL and bortezomib as compared with cells treated with TRAIL alone. Thus, all downstream components of the pathway (Bid cleavage, cytochrome c release, and caspase-3 activation) were amplified. These data strongly suggest that p21-mediated cdk inhibition promotes TRAIL sensitivity via caspase-8 activation and that TRAIL and bortezomib should be combined in appropriate in vivo models as a possible approach to solid tumor therapy.
Two Functional Epitopes of Pigment Epithelial–Derived Factor Block Angiogenesis and Induce Differentiation in Prostate Cancer
Authors: Filleur Stephanie , Volz Karl , Nelius Thomas , Mirochnik Yelena , Huang Hanhua , Zaichuk Tetiana A. , Aymerich Maria S. , Becerra Sofia P. , Yap Ronald , Veliceasa Dorina , Shroff Emelyn H. , Volpert Olga V. 
Published: September 2005

Abstract
Pigment epithelial-derived factor (PEDF), an angiogenesis inhibitor with neurotrophic properties, balances angiogenesis in the eye and blocks tumor progression. Its neurotrophic function and the ability to block vascular leakage is replicated by the PEDF 44-mer peptide (residues 58-101). We analyzed PEDFs' three-dimensional structure and identified a potential receptor-binding surface. Seeking PEDF-based antiangiogenic agents we generated and tested peptides representing the middle and lower regions of this surface. We identified previously unknown antiangiogenic epitopes consisting of the 34-mer (residues 24-57) and a shorter proximal peptide (TGA, residues 16-26) with the critical stretch L19VEEED24 and a fragment within the 44-mer (ERT, residues 78-94), which retained neurotrophic activity. The 34-mer and TGA, but not the 44-mer reproduced PEDF angioinhibitory signals hinged on c-jun-NH2-kinase–dependent nuclear factor of activated T cell deactivation and caused apoptosis. Conversely, the ERT, but not the 34-mer/TGA induced neuronal differentiation. For the 44-mer/ERT, we showed a novel ability to cause neuroendocrine differentiation in prostate cancer cells. PEDF and the peptides bound endothelial and PC-3 prostate cancer cells. Bound peptides were displaced by PEDF, but not by each other, suggesting multiple receptors. PEDF and its active fragments blocked tumor formation when conditionally expressed by PC-3 cells. The 34- and 44-mer used distinct mechanisms: the 34-mer acted on endothelial cells, blocked angiogenesis, and induced apoptosis whereas 44-mer prompted neuroendocrine differentiation in cancer cells. Our results map active regions for the two PEDF functions, signaling via distinct receptors, identify candidate peptides, and provide their mechanism of action for future development of PEDF-based tumor therapies.
A Novel Ring-Substituted Diindolylmethane,1,1-Bis[3′-(5-Methoxyindolyl)]-1-(p-t-Butylphenyl) Methane, Inhibits Extracellular Signal-Regulated Kinase Activation and Induces Apoptosis in Acute Myelogenous Leukemia
Authors: Contractor Rooha , Samudio Ismael J. , Estrov Zeev , Harris David , McCubrey James A. , Safe Stephen H. , Andreeff Michael , Konopleva Marina 
Published: September 2005

Abstract
We investigated the antileukemic activity and molecular mechanisms of action of a newly synthesized ring-substituted diindolylmethane derivative, 1,1-bis[3′-(5-methoxyindolyl)]-1-(p-t-butylphenyl) methane (DIM #34), in acute myelogenous leukemia (AML) cells. DIM #34 inhibited AML cell growth via the induction of apoptosis and abrogated clonogenic growth of primary AML samples. Exposure to DIM #34 induced loss of mitochondrial inner transmembrane potential, release of cytochrome c into the cytosol, and caspase activation. Bcl-2–overexpressing, Bax knockout, and caspase-9–deficient cells were partially resistant to cell death, suggesting the involvement of the intrinsic apoptotic pathway. Furthermore, DIM #34 transiently inhibited the phosphorylation and activity of the extracellular signal-regulated kinase and abrogated Bcl-2 phosphorylation. Because other methylene-substituted diindolylmethane analogues have been shown to transactivate the nuclear receptor peroxisome proliferator-activated receptor γ (PPARγ), we studied the role of PPARγ in apoptosis induction. Cotreatment of cells with a selective PPARγ antagonist or with retinoid X receptor and retinoic acid receptor ligands partially modulated apoptosis when combined with DIM #34, suggesting PPARγ receptor-dependent and receptor-independent cell death. Together, these findings suggest that diindolylmethanes are a new class of compounds that selectively induce apoptosis in AML cells through the modulation of the extracellular signal-regulated kinase and PPARγ signaling pathways.
Haplotype Loss of HLA Class I Antigen as an Escape Mechanism from Immune Attack in Lung Cancer
Authors: So Tetsuya , Takenoyama Mitsuhiro , Mizukami Makiko , Ichiki Yoshinobu , Sugaya Masakazu , Hanagiri Takeshi , Sugio Kenji , Yasumoto Kosei 
Published: September 2005

AbstractOne of tumor escape mechanisms from the host's immunosurveillance system (i.e., a haplotype loss of HLA class I antigens) has been detected in various tumor cells. We hypothesize that the majority of tumor cells with normal HLA class I expression were attacked and eradicated by CTLs, and only a minority with an abnormal expression of HLA class I antigens could escape the host's immunosurveillance system. Using HLA class I–transfected tumor variants as stimulators in A904L lung cancer cell line, which has a haplotype loss of HLA class I antigens, both the transfected HLA-A26 and HLA-B39–restricted CTL lines were induced from autologous lymphocytes. However, only one HLA-B39–restricted CTL clone (CTL G3b) was established, and it was then used to identify the antigen. SGT1B [suppressor of G2 allele of SKP1 (SGT1), suppressor of kinetochore protein (SKP1)] was identified as the antigen recognized by CTL G3b. Further experiments using 13 subclones from a primary culture of A904L were found to confirm our above-mentioned hypothesis. Tumor cells with a normal HLA class I expression may thus be killed by CTL at an early stage of carcinogenesis, and only tumor cells with a haplotype loss of HLA class I antigens can escape an immune attack and develop into clinical cancer.
Recovery of CD8+ T-Cell Function During Systemic Chemotherapy in Advanced Ovarian Cancer
Authors: Coleman Sharon , Clayton Aled , Mason Malcolm D. , Jasani Bharat , Adams Malcolm , Tabi Zsuzsanna 
Published: September 2005

Abstract
Immunologic approaches are emerging as new treatment options in several types of cancer. However, whereas the ability of patients to develop potent CD8+ T-cell responses is crucial for efficient antitumor responses, immunocompetence and T-cell function are not tested routinely in patients entering immunotherapy. The objective of our study was to monitor T-cell function in advanced cancer and during chemotherapy. CD8+ T-cell function of 21 patients with advanced ovarian cancer (stages III-IV) was assessed by cytokine flow cytometry following stimulation of 42 PBMC samples with a panel of synthetic viral peptides in vitro, consisting of pan-Caucasian epitopes. CD8+ T-cell responses were significantly lower in patients with high levels (&gt;200 units/mL) of Ca125 (marker of tumor load and progression) than in those with low Ca125 levels (P = 0.0013). In longitudinal studies of nine patients, chemotherapy was associated with decreasing Ca125 levels in seven cases and also with improvement or maintenance of CD8+ T-cell function in seven cases. After the full course of chemotherapy, five of nine patients in remission displayed potent CD8+ T-cell responses, whereas four of nine patients in progression displayed low or decreasing T-cell responses, pointing toward a correlation between T-cell function and clinical response. Our results show for the first time that CD8+ T-cell function is not permanently suppressed in advanced cancer and successful chemotherapy is associated with improved antigen-specific T-cell reactivity. We suggest that functional assays determining T-cell immunocompetence can be valuable tools for optimizing cancer immunotherapy for improved clinical success.
Genetic Polymorphism in Cytochrome P450 7A1 and Risk of Colorectal Cancer: The Fukuoka Colorectal Cancer Study
Authors: Hagiwara Tomoko , Kono Suminori , Yin Guang , Toyomura Kengo , Nagano Jun , Mizoue Tetsuya , Mibu Ryuichi , Tanaka Masao , Kakeji Yoshihiro , Maehara Yoshihiko , Okamura Takeshi , Ikejiri Kouji , Futami Kitaroh , Yasunami Youichi , Maekawa Takafumi , Takenaka Kenji , Ichimiya Hitoshi , Imaizumi Nobutoshi 
Published: September 2005

Abstract
Bile acids have long been implicated in the etiology of colorectal cancer, but epidemiologic evidence remains elusive. Cholesterol 7α-hydroxylase (CYP7A1) is the rate-limiting enzyme in the synthesis of bile acids from cholesterol in the liver, and thus may be an important determinant of bile acid production. We examined the association between the CYP7A1 A-203C polymorphism and colorectal cancer. The CYP7A1 A-203C polymorphism was determined by the PCR-RFLP method in 685 incident cases of colorectal cancer and 778 controls randomly selected from a community in the Fukuoka area, Japan. The CC genotype was slightly less frequent in the case group, and the adjusted odds ratio for the CC versus AA genotype was 0.88 (95% confidence interval, 0.65-1.20). In the analysis by subsite of the colorectum, a decreased risk associated with the CYP7A1 CC genotype was observed for proximal colon cancer, but not for either distal colon or rectal cancer. The adjusted odds ratios (95% confidence intervals) of proximal colon cancer for the CC genotype were 0.63 (0.36-1.10) compared with the AA genotype, and 0.59 (0.37-0.96) compared with the AA and AC genotypes combined. A decreased risk of proximal colon cancer in relation to the CC genotype of CYP7A1 A-203C, which probably renders less activity of the enzyme converting cholesterol to bile acids, is new evidence for the role of bile acids in colorectal carcinogenesis.
The Proinflammatory Cytokine Interleukin 1β and Hypoxia Cooperatively Induce the Expression of Adrenomedullin in Ovarian Carcinoma Cells through Hypoxia Inducible Factor 1 Activation
Authors: Frede Stilla , Freitag Patricia , Otto Teresa , Heilmaier Christina , Fandrey Joachim 
Published: September 2005

Abstract
Adrenomedullin (ADM) is a potent hypotensive peptide produced by macrophages and endothelial cells during ischemia and sepsis. The molecular mechanisms that control ADM gene expression in tumor cells are still poorly defined. It is known, however, that hypoxia potently increases ADM expression by activation of the transcription factor complex hypoxia inducible factor 1 (HIF-1). Proinflammatory cytokines produced by tumor invading macrophages likewise activate expression of ADM. Herein, we show that apart from hypoxia, the proinflammatory cytokine interleukin 1β (IL-1β) induced the expression of ADM mRNA through activation of HIF-1 under normoxic conditions and enhanced the hypoxia-induced expression in the human ovarian carcinoma cell line OVCAR-3. IL-1β significantly increased accumulation and nuclear translocation of HIF-1α under normoxic conditions and amplified hypoxic HIF-1 activation. IL-1β treatment affected neither HIF-1α mRNA levels nor the hydroxylation status of HIF-1α and, thus, stability of the protein. Instead cycloheximide effectively prevented the increase in HIF-1α protein, indicating a stimulatory effect of IL-1β on HIF-1α translation. Finally, treatment of HIF-1α with short interfering RNA revealed a significant role for HIF-1 in the IL-1β–dependent stimulation of ADM expression.
Androgen Receptor Cytosine, Adenine, Guanine Repeats, and Haplotypes in Relation to Ovarian Cancer Risk
Authors: Terry Kathryn L. , De Vivo Immaculata , Titus-Ernstoff Linda , Shih Mei-Chiung , Cramer Daniel W. 
Published: September 2005

AbstractBiological and epidemiologic evidence suggest that androgen or its receptor may play a role in ovarian cancer pathogenesis. The most notable genetic factor influencing androgen receptor (AR) activity is the functional cytosine, adenine, guanine (CAG) repeat in which length is inversely proportional to its transactivational activity. Additional genetic variation due to single nucleotide polymorphisms in the AR gene may be captured through haplotypes. We genotyped the CAG microsatellite and six haplotype-tagging single nucleotide polymorphisms (rs962458, rs6152, rs1204038, rs2361634, rs1337080, rs1337082) of the androgen receptor gene in 987 ovarian cancer cases and 1,034 controls from a study conducted in New Hampshire and eastern Massachusetts between May 1992 and July 2003. We estimated haplotype frequencies and calculated odds ratios with 95% confidence intervals to evaluate the association between the haplotypes and the AR CAG microsatellite with ovarian cancer risk. We observed that carriage of two alleles with ≥22 CAG repeats was associated with an increased risk of ovarian cancer compared with carriage of two alleles with &lt;22 CAG repeats (covariate-adjusted odds ratios, 1.31; 95% confidence intervals, 1.01-1.69). Five common haplotypes in the AR gene were identified, but no association between these and ovarian cancer risk was observed. Our results suggest that possession of two long AR alleles (≥22 CAG repeats) may be associated with increased risk of ovarian cancer compared with women with two short AR alleles (&lt;22 CAG repeats).
Hsp70-Like Protein 1 Fusion Protein Enhances Induction of Carcinoembryonic Antigen–Specific CD8+ CTL Response by Dendritic Cell Vaccine
Authors: Wu Yanfeng , Wan Tao , Zhou Xiangyang , Wang Baomei , Yang Feng , Li Nan , Chen Guoyou , Dai Shengming , Liu Shuxun , Zhang Minghui , Cao Xuetao 
Published: September 2005

AbstractHeat shock proteins (HSP) have been revealed to interact with antigen-presenting cells and have potent adjuvant capability to induce antigen-specific CD8+ CTL and Th1 responses. Our previous work shows how Hsp70-like protein 1 (Hsp70L1), as a new member of the Hsp70 subfamily, acts as potent Th1 adjuvant. Here, we report the efficient induction of tumor antigen-specific immune response by dendritic cells pulsed with recombinant fusion protein of Hsp70L1 and CEA576-669 fragment of the carcinoembryonic antigen (CEA) containing CAP-1 (a HLA-A2–restricted CTL epitope). Fusion protein CEA576-669-Hsp70L1 can promote dendritic cell maturation and activate dendritic cells to produce cytokines, such as interleukin-12, interleukin-1β, and tumor necrosis factor-α, and chemokines, such as macrophage inflammatory protein-1α, macrophage inflammatory protein-1β, and regulated on activation, normal T expressed and secreted, indicating the adjuvant ability of Hsp70L1 in the fusion protein. CEA-specific HLA-A2.1–restricted CD8+ CTLs either from patients with CEA+/HLA-A2.1+ colon carcinoma or from splenocytes of immunized HLA-A2.1/Kb transgenic mice can be generated more efficiently after stimulations or immunizations with dendritic cells pulsed by CEA576-669-Hsp70L1 than with dendritic cells pulsed by CEA576-669 alone, resulting in secreting more Th1 cytokine IFN-γ and killing target cells more potently in an antigen-specific and HLA-A2.1–restricted manner. Adoptive transfer of splenocytes from transgenic mice immunized with CEA576-669-Hsp70L1–pulsed dendritic cells can inhibit tumor growth and prolong survival in nude mice bearing CEA+/HLA-A2.1+ human colon carcinoma more markedly. Therefore, Hsp70L1 has potent adjuvant effect in form of fusion protein, indicating that Hsp70L1 may be widely used as Th1 adjuvant to prepare antigenic fusion protein for the therapeutics of cancer or infectious diseases.
Nanoparticle Targeting of Anticancer Drug Improves Therapeutic Response in Animal Model of Human Epithelial Cancer
Authors: Kukowska-Latallo Jolanta F. , Candido Kimberly A. , Cao Zhengyi , Nigavekar Shraddha S. , Majoros Istvan J. , Thomas Thommey P. , Balogh Lajos P. , Khan Mohamed K. , Baker James R. 
Published: September 2005

Abstract
Prior studies suggested that nanoparticle drug delivery might improve the therapeutic response to anticancer drugs and allow the simultaneous monitoring of drug uptake by tumors. We employed modified PAMAM dendritic polymers &lt;5 nm in diameter as carriers. Acetylated dendrimers were conjugated to folic acid as a targeting agent and then coupled to either methotrexate or tritium and either fluorescein or 6-carboxytetramethylrhodamine. These conjugates were injected i.v. into immunodeficient mice bearing human KB tumors that overexpress the folic acid receptor. In contrast to nontargeted polymer, folate-conjugated nanoparticles concentrated in the tumor and liver tissue over 4 days after administration. The tumor tissue localization of the folate-targeted polymer could be attenuated by prior i.v. injection of free folic acid. Confocal microscopy confirmed the internalization of the drug conjugates into the tumor cells. Targeting methotrexate increased its antitumor activity and markedly decreased its toxicity, allowing therapeutic responses not possible with a free drug.
CK2 Inhibits Apoptosis and Changes Its Cellular Localization Following Ionizing Radiation
Authors: Yamane Kazuhiko , Kinsella Timothy J. 
Published: September 2005

Abstract
In this study, we show that CK2 (casein kinase II, CKII) participates in apoptotic responses following ionizing radiation (IR). Using HeLa human cervical carcinoma cells, we find that transfection of small interfering RNA against the CK2 α and/or α′ catalytic subunits results in enhanced apoptosis following IR damage as measured by flow cytometry techniques, compared with a control small interfering RNA. Within 2 to 6 hours of IR, CK2 α partially localizes to perinuclear structures, whereas a marked nuclear localization of α′ occurs. Treatment with a pan-caspase inhibitor or transfection of ARC (apoptosis repressor with caspase recruitment domain) suppresses the apoptotic response to IR in the CK2-reduced cells, indicating involvement of caspases. Additionally, we find that CK2 α and/or α′ reduction affects cell cycle progression independent of IR damage in this human cell line. However, the G2-M checkpoint following IR is not affected in CK2 α- and/or α′-reduced cells. Thus, our data suggest that CK2 participates in inhibition of apoptosis and negatively regulates caspase activity following IR damage.
A Cell Proliferation Signature Is a Marker of Extremely Poor Outcome in a Subpopulation of Breast Cancer Patients
Authors: Dai Hongyue , van't Veer Laura , Lamb John , He Yudong D. , Mao Mao , Fine Bernard M. , Bernards Rene , van de Vijver Marc , Deutsch Paul , Sachs Alan , Stoughton Roland , Friend Stephen 
Published: September 2005

Abstract
Breast cancer comprises a group of distinct subtypes that despite having similar histologic appearances, have very different metastatic potentials. Being able to identify the biological driving force, even for a subset of patients, is crucially important given the large population of women diagnosed with breast cancer. Here, we show that within a subset of patients characterized by relatively high estrogen receptor expression for their age, the occurrence of metastases is strongly predicted by a homogeneous gene expression pattern almost entirely consisting of cell cycle genes (5-year odds ratio of metastasis, 24.0; 95% confidence interval, 6.0-95.5). Overexpression of this set of genes is clearly associated with an extremely poor outcome, with the 10-year metastasis-free probability being only 24% for the poor group, compared with 85% for the good group. In contrast, this gene expression pattern is much less correlated with the outcome in other patient subpopulations. The methods described here also illustrate the value of combining clinical variables, biological insight, and machine-learning to dissect biological complexity. Our work presented here may contribute a crucial step towards rational design of personalized treatment.