bluuebunny/crossref_metadata_2025_split huggingface dataset:
Interleukin 1β Enhances Invasive Ability of Gastric Carcinoma through Nuclear Factor-κB Activation
Authors: Yamanaka Naoki , Morisaki Takashi , Nakashima Hiroshi , Tasaki Akira , Kubo Makoto , Kuga Hirotaka , Nakahara Chihiro , Nakamura Katsuya , Noshiro Hirokazu , Yao Takashi , Tsuneyoshi Masazumi , Tanaka Masao , Katano Mitsuo 
Published: September 2005

AbstractPurpose: We examined the role of interleukin (IL)-1β in activation of nuclear factor κB (NF-κB) and the biological function of activated NF-κB in gastric carcinoma cells.Experimental Design: Human gastric carcinoma cell line GCTM-1 was used to examine NF-κB activation by immunostaining and electrophoretic mobility shift assay. Matrix metalloproteinase (MMP)-9 expression, which plays an important role in tumor invasion, was assessed by semiquantitative reverse transcription-PCR, Western blotting, and immunostaining. The invasive ability of GCTM-1 cells was measured by Matrigel invasion assay. In vivo expression of IL-1β and MMP-9 and activation of NF-κB in 10 surgically resected gastric carcinoma specimens were examined immunohistochemically.Results: IL-1β enhanced NF-κB activation, MMP-9 expression, and the invasive ability of GCTM-1. A NF-κB inhibitor, pyrrolidine dithiocarbamate, suppressed both MMP-9 expression and invasiveness of IL-1β-treated GCTM-1 cells. IL-1β did not increase the invasive ability of GCTM-1 cells transfected with MMP-9 antisense oligonucleotide. Concomitant expression of IL-1β and nuclear NF-κB was observed in 3 of 10 gastric carcinoma specimens. Cells producing IL-1β were tumor-infiltrating macrophages in two specimens and gastric carcinoma cells in one specimen.Conclusions: One of the molecules that may play a role in NF-κB activation in some gastric carcinomas is IL-1β. The present results suggest that IL-1β increases the invasive ability of carcinoma cells through activation of NF-κB and the resulting MMP-9 expression.
Intratumoral Administration of Recombinant Human Interleukin 12 in Head and Neck Squamous Cell Carcinoma Patients Elicits a T-Helper 1 Profile in the Locoregional Lymph Nodes
Authors: van Herpen Carla M. , Looman Maaike , Zonneveld Marijke , Scharenborg Nicole , de Wilde Peter C. , van de Locht Louis , Merkx Matthias A. W. , Adema Gosse J. , De Mulder Pieter H. 
Published: September 2005

Abstract
The objective of this Phase II study was to evaluate the pharmacodynamic and immune effects of intratumorally administered recombinant human interleukin-12 (IL-12) on regional lymph nodes, primary tumor, and peripheral blood. Ten previously untreated patients with head and neck squamous cell carcinoma were injected in the primary tumor two to three times, once/week, at two dose levels of 100 or 300 ng/kg, before surgery. We compared these patients with 20 control (non-IL-12-treated) patients. Toxicity was high, with unexpected dose-limiting toxicities at the 300 ng/kg dose level. Dose-dependent plasma IFN-γ and IL-10 increments were detected. These cytokine levels were higher after the first injection than after the subsequent injections. A rapid, transient reduction in lymphocytes, monocytes, and all lymphocyte subsets, especially natural killer cells, was observed, due to a redistribution to the lymph nodes. In the enlarged lymph nodes of the IL-12-treated patients, a higher percentage of natural killer cells and a lower percentage of T-helper cells were found compared with control patients. The same pattern was detected in the infiltrate in the primary tumor. Real-time semiquantitative PCR analysis of peripheral blood mononuclear cells in the peripheral blood showed a transient decrease of T-bet mRNA. Interestingly, the peripheral blood mononuclear cells in the lymph nodes showed a 128-fold (mean) increase of IFN-γ mRNA. A switch from the Th2 to a Th1 profile in the lymph nodes compared with the peripheral blood occurred in the IL-12-treated patients. In conclusion, in previously untreated head and neck squamous cell carcinoma patients, recombinant human IL-12 intratumorally showed dose-limiting toxicities at the dose level of 300 ng/kg and resulted in measurable immunological responses locoregionally at both dose levels.
Phase I and Pharmacokinetic Study of Irofulven Administered Weekly or Biweekly in Advanced Solid Tumor Patients
Authors: Alexandre Jérôme , Raymond Eric , Kaci Mahmoud Ould , Brain Etienne C. , Lokiec François , Kahatt Carmen , Faivre Sandrine , Yovine Alejandro , Goldwasser François , Smith Sheri L. , MacDonald John R. , Misset Jean-Louis , Cvitkovic Esteban 
Published: September 2005

AbstractPurpose: We performed a Phase I and pharmacokinetic study to determine the maximum tolerated dose of irofulven (6-hydroxymethylacylfulvene; MGI-114, MGI PHARMA, Inc.), administered in intermittent weekly schedules in patients with advanced solid tumors.Experimental Design: Three schedules were tested: A, days 1, 8, and 15 every 4 weeks; B, days 1 and 8 every 3 weeks; C, days 1 and 15 every 4 weeks. Drugs were administered as 5- and 30-min (schedules B and C) infusions. Dose levels of 10, 12, and 14 mg/m2/week were explored.Results: Ninety-nine patients received 256 cycles. Fifteen of 74 patients evaluable for maximum tolerated dose experienced 16 dose-limiting toxicities (5 of 17 patients on schedule A, 2 of 25 on schedule B, and 8 of 32 on schedule C), principally treatment delay for thrombocytopenia. Schedule A was considered unsuitable because of frequent thrombocytopenia and treatment discontinuations. Twenty-three percent of the overall population (22 patients with grade 1–2, and 1 patient with grade 3), including 37% of patients on dose level 3, experienced unexpected dose-limiting visual toxicity, which included color perception and visual field alterations linked to retinal cone cell toxicity; the visual toxicity had an early onset, was mostly reversible, and was related to higher dose per infusion. Safety profiles were similar for 5- and 30-min infusions. The relationships between dose and area under the plasma concentration–time curve and maximum plasma concentration were linear for both 5- and 30-min infusions in the 78 patients evaluated for pharmacokinetics. The area under the plasma concentration–time curve and clearance were comparable between infusion durations. Responses included one complete (ovarian), one partial (renal), and seven disease stabilizations lasting &gt;4 months.Conclusions: We recommend doses of 18 mg/m2/infusion for schedule B and 24 mg/m2/infusion for schedule C, limited to 0.55 mg/kg and a total dose of 50 mg/infusion, administered over 30-min.
Intratumoral Administration of Dendritic Cells Overexpressing CCL21 Generates Systemic Antitumor Responses and Confers Tumor Immunity
Authors: Yang Seok-Chul , Hillinger Sven , Riedl Karen , Zhang Ling , Zhu Li , Huang Min , Atianzar Kimberly , Kuo Brian Y. , Gardner Brian , Batra Raj K. , Strieter Robert M. , Dubinett Steven M. , Sharma Sherven 
Published: September 2005

Abstract
To achieve in situ tumor antigen uptake and presentation, intratumoral administration of ex vivo-generated, gene-modified murine bone marrow-derived dendritic cells (DC) was used in a murine lung cancer model. To attract mature host DC and activated T cells at the tumor site, the DC were transduced with an adenoviral vector expressing secondary lymphoid tissue chemokine (CCL21/SLC). Sixty percent of the mice treated with 106 DC-AdCCL21 intratumorally (7–10 ng/ml/106 cells/24 h of CCL21) at weekly intervals for 3 weeks showed complete tumor eradication, whereas only 25% of mice had complete resolution of tumors when mice were treated with fibroblasts expressing CCL21. In contrast only 12% of the mice treated with unmodified or control vector modified DC (DC-AdCV) showed complete tumor eradication. DC-AdCCL21 administration led to increases in the CD4+, CD8+, and CD3+CXCR3+ T cells, as well as DC expressing CD11c+ DEC205+. CD4+CD25+ T-regulatory cells infiltrating the tumors were markedly reduced after DC-AdCCL21 therapy. The tumor site cellular infiltrates were accompanied by the enhanced elaboration of granulocyte macrophage colony-stimulating factor, IFN-γ, MIG/CXCL9, IP-10/CXCL10, and interleukin 12, but decreases in the immunosuppressive mediators transforming growth factor β and prostaglandin E2. DC-AdCCL21-treated tumor-bearing mice showed enhanced frequency of tumor-specific T lymphocytes secreting IFN-γ, and tumor protective immunity was induced after DC-AdCCL21 therapy. In vivo depletion of IP-10/CXCL10, MIG/CXCL9, or IFN-γ significantly reduced the antitumor efficacy of DC-AdCCL21. These findings provide a strong rationale for the evaluation of DC-AdCCL21 in cancer immunotherapy.
Real-Time Gap Ligase Chain Reaction
Authors: Harden Susan V. , Thomas David C. , Benoit Nicole , Minhas Khalid , Westra William H. , Califano Joseph A. , Koch Wayne , Sidransky David 
Published: September 2005

AbstractPurpose: We have developed a real-time semiquantitative gap ligase chain reaction for detecting p53 point mutations at low level in a background of excess of wild-type DNA.Experimental Design: This method was validated by direct comparison to a previously validated but cumbersome phage plaque hybridization assay. Forty-one surgical margins and lymph nodes from 10 cases of head and neck squamous cell carcinoma and lung carcinoma were tested for p53 mutant clones.Results: Both methods detected p53 mutants in margins from 8 of the 10 cases, whereas standard pathology detected cancer cells in only 3 cases. Positive margins included tissue samples with a tumor/normal DNA ratio of up to 1:1000.Conclusions: This novel molecular approach can be performed in &lt;5 h facilitating intraoperative use for real-time surgical resection.
Immunomagnetic Detection and Clinical Significance of Micrometastatic Tumor Cells in Malignant Melanoma Patients
Authors: Faye Ragnar S. , Aamdal Steinar , Høifødt Hanne K. , Jacobsen Erling , Holstad Linn , Skovlund Eva , Fodstad Øystein 
Published: September 2005

Abstract
Purpose: Positive associations between the presence of micrometastatic tumor cells and disease aggressiveness have been reported in several tumor types, but the clinical implications are still not established. We wanted to test a new, sensitive immunomagnetic detection method on bone marrow (BM) and peripheral blood (PB) samples from patients with malignant melanoma and relate the findings to clinical outcome.
Experimental Design: Samples from 210 patients admitted for relapse of cutaneous melanoma were examined. Mononuclear cell fractions isolated from BM and PB were incubated with superparamagnetic particles coated with antimelanoma antibodies. Live tumor cells with bound beads were isolated with a magnet and identified in a microscope as cell-bead rosettes. Beads without antibody or with an irrelevant antibody were used as controls. The whole procedure was completed within 2–3 h. The identity of the cells was confirmed with a new double labeling procedure with fluorescent microparticles.
Results: Rosetted melanoma cells were found in BM aspirates of 35 of 186 (19%) patients, but in only 2 of 208 (1%) PB samples. The controls were all negative. After a median observation time of 1.1 year (range, 0–6.8 years), patients with tumor cells in BM showed a significantly shorter overall survival from time of BM aspiration (P = 0.009). In multiple regression analysis, a positive BM test was a strong indicator of overall survival (P = 0.021), associated with disease stage (American Joint Committee on Cancer) and with the number of metastatic sites, but not with the primary (Breslow) tumor depth and morphology.
Conclusions: The results demonstrate the prognostic significance of detecting BM micrometastasis in melanoma patients. The results strengthen the validity of the immunobead technique. In contrast to other techniques, the method identifies intact, live tumor cells that can be further characterized, making the assay attractive for extended use.
Development of a New Isogenic Cell-Xenograft System for Evaluation of NAD(P)H:Quinone Oxidoreductase-Directed Antitumor Quinones
Authors: Dehn Donna L. , Winski Shannon L. , Ross David 
Published: September 2005

Abstract
Purpose: The purpose of our study was to develop and validate an isogenic cell line pair that differs only in the expression of NAD(P)H:quinone oxidoreductase (NQO1) that can be used to examine the in vitro and in vivo role of NQO1 in the bioactivation of the antitumor quinone RH1 (2,5-diaziridinyl-3-(hydroxymethyl)-6-methyl-1,4-benzoquinone), a compound currently in Phase I clinical trials.
Experimental Design: MDA-MB-468 (MDA468) human breast adenocarcinoma cells, homozygous for a polymorphism in NQO1 (NQO1*2/*2) and with low levels of NQO1 activity, were stably transfected with human NQO1 to generate a clone (NQ16) expressing very high NQO1 activity. We examined levels of other reductases and looked at biochemical systems that might influence response to antitumor quinones to validate that the isogenic cell line pair differed only in the expression of NQO1. The 3-(4,5-dimethylthiazol-2,5-diphenyl)tetrazolium (MTT) assay was used to determine the differential toxicity of various quinones, including the most recent NQO1-directed antitumor quinone, RH1, between the two cell lines. Human tumor xenografts were established from both MDA468 and NQ16 cells, and the antitumor activity of RH1 was evaluated.
Results: Levels of cytochrome P450 reductase, cytochrome b5 reductase, soluble thiols, and superoxide dismutase in the NQ16 line were unchanged from the parental line. The functional significance of wild-type NQO1 expression was confirmed by measurement of the differential toxicity of compounds activated or deactivated by NQO1 in the two cell lines. The toxicity of the NQO1-directed antitumor quinones RH1 and streptonigrin were markedly greater and the toxicity of menadione, which is detoxified by NQO1, was ameliorated in the NQ16 line. High levels of NQO1 expression were observed throughout xenograft tumors established from the NQ16 cell line. RH1 treatment was effective at statistically reducing tumor volume in NQ16 xenografts at all of the doses tested [0.1, 0.2, 0.4 mg/kg every day for 5 days), whereas only the highest dose of RH1 resulted in a significant reduction in tumor volume in MDA468 xenografts.
Conclusions: The MDA468/NQ16 isogenic cell line pair is a useful model system for evaluating the role of NQO1 in the bioactivation of antitumor quinones in both cell lines and xenografts. In addition, our data demonstrate that the novel antitumor quinone RH1, is effectively activated by NQO1 both in vitro and in vivo.
Trastuzumab (Herceptin) Enhances Class I-Restricted Antigen Presentation Recognized by HER-2/neu-Specific T Cytotoxic Lymphocytes
Authors: Kono Koji , Sato Eiji , Naganuma Hirofumi , Takahashi Akihiro , Mimura Kousaku , Nukui Hideaki , Fujii Hideki 
Published: September 2005

AbstractPurpose: Numerous examples from animal models and clinical trials showed that HER-2-derived peptides are naturally processed as a CTL epitope and can be recognized by tumor-specific CTLs in several tumors with HER-2 overexpression. The humanized anti-HER-2 monoclonal antibody, Herceptin, has been designed to specifically antagonize the HER-2 function by directing against the extracellular domain of the HER-2 protein. One of the actions of Herceptin includes the internalization and degradation of HER-2, which might increase the amount of HER-2-derived peptides available for loading to MHC class I.Experimental Design: In the present study, we investigated how Herceptin treatment of HER-2-overexpressing targets affects lysis by HER-2-specific CTLs.Results: We showed that Herceptin sensitized HER-2-overexpressing tumors to lysis by HLA-A2-restricted or HLA-A24-restricted CTLs, without any effect of the expression of MHC class I, costimulatory molecules, adhesion molecules, or TAP-1 on the targets. Furthermore, the enhancement of cytolytic activity with Herceptin was inhibited by addition of a specific proteasome inhibitor, lactacystin.Conclusions: These results suggested that Herceptin treatment might enhance the class I-restricted presentation of endogenous HER-2 antigen via the proteasome step, resulting in higher susceptibility of HER-2-overexpressing tumors to lysis by the HER-2-specific CTLs.
Expression of Vascular Endothelial Growth Factor Receptor-3 by Lymphatic Endothelial Cells Is Associated with Lymph Node Metastasis in Prostate Cancer
Authors: Zeng Yiping , Opeskin Kenneth , Baldwin Megan E. , Horvath Lisa G. , Achen Marc G. , Stacker Steven A. , Sutherland Robert L. , Williams Elizabeth D. 
Published: September 2005

Abstract
Purpose: The molecular mechanisms underlying lymph node metastasis are poorly understood, despite the well-established clinical importance of lymph node status in many human cancers. Recently, vascular endothelial growth factor (VEGF)-C and VEGF-D have been implicated in the regulation of tumor lymphangiogenesis and enhancement of lymphatic invasion via activation of VEGF receptor-3. The purpose of this study was to determine the expression pattern of the VEGF-C/VEGF-D/VEGF receptor-3 axis in prostate cancer and its relationship with lymph node metastasis.
Experimental Design: The expression pattern of VEGF-C, VEGF-D, and VEGF receptor-3 in localized prostate cancer specimens (n = 37) was determined using immunohistochemistry.
Results: Widespread, heterogeneous staining for VEGF-C and VEGF-D was observed in all cancer specimens. Intensity of VEGF-C staining was lower in benign prostate epithelium than in adjacent carcinoma, whereas no difference between benign epithelium and carcinoma was observed for VEGF-D staining. VEGF receptor-3 immunostaining was detected in endothelial cells of lymphatic vessels in 18 of 37 tissue samples. The presence of VEGF receptor-3-positive vessels was associated with lymph node metastasis (P = 0.0002), Gleason grade (P &lt; 0.0001), extracapsular extension (P = 0.0382), and surgical margin status (P = 0.0069). In addition, VEGF receptor-3 staining highlighted lymphatic invasion by VEGF-C-positive/VEGF-D-positive carcinoma cells.
Conclusions: Together, these results suggest that paracrine activation of lymphatic endothelial cell VEGF receptor-3 by VEGF-C and/or VEGF-D may be involved in lymphatic metastasis. Thus the VEGF-C/VEGF-D/VEGF receptor-3 signaling pathway may provide a target for antilymphangiogenic therapy in prostate cancer.
Clinical Significance of Thrombospondin 1 Expression in Hepatocellular Carcinoma
Authors: Poon Ronnie T. , Chung Ka Kit , Cheung Siu Tim , Lau Cecilia P. , Tong See Wai , Leung Ka Ling , Yu Wan Ching , Tuszynski George P. , Fan Sheung Tat 
Published: September 2005

Abstract
Purpose: Thrombospondin 1 (THBS 1) is a matricellular protein capable of modulating angiogenesis. However, the actual role of THBS 1 in angiogenesis and tumor progression remains controversial. Hepatocellular carcinoma (HCC) is a hypervascular tumor characterized by neovascularization. The significance of THBS 1 in HCC remains unknown. In this study, the significance of THBS 1 in HCC was evaluated by correlating its expression with clinicopathological data. The possible role of THBS 1 in the angiogenesis of HCC was also studied by correlating its expression with vascular endothelial growth factor (VEGF) expression.
Experimental Design: Sixty HCC patients were recruited in this study. THBS 1 and VEGF protein expression in tumorous livers were localized by immunohistochemical staining and quantified by ELISA. THBS 1 mRNA was quantified by quantitative reverse transcription-PCR.
Results: Immunohistochemical staining of THBS 1 was positive in HCC cells in 51.7% of patients and in stromal cells in 65% of patients. Tumor THBS 1 protein level was significantly correlated with its mRNA expression (P = 0.001) and was significantly correlated with tumor VEGF protein levels (P = 0.001). Its expression was significantly associated with the presence of venous invasion (P = 0.008) and advanced tumor stage (P = 0.049). High THBS 1 expression was also a prognostic marker of poor survival in HCC patients.
Conclusions: This study shows that high expression of THBS 1 is associated with tumor invasiveness and progression in HCC. THBS 1 appears to be a proangiogenic factor that stimulates angiogenesis in HCC in view of its positive correlation with VEGF expression.
Phase II Study of Celecoxib and Trastuzumab in Metastatic Breast Cancer Patients Who Have Progressed after Prior Trastuzumab-Based Treatments
Authors: Dang Chau T. , Dannenberg Andrew J. , Subbaramaiah Kotha , Dickler Maura N. , Moasser Mark M. , Seidman Andrew D. , D’Andrea Gabriella M. , Theodoulou Maria , Panageas Katherine S. , Norton Larry , Hudis Clifford A. 
Published: September 2005

Abstract
Purpose: Preclinical studies demonstrate a link between overexpression of HER-2/neu and cyclooxygenase-2 (COX-2) activity. To explore the possibility that COX-2 is a therapeutic target, we conducted a phase II study of celecoxib, a selective COX-2 inhibitor, and trastuzumab in patients with HER-2/neu-overexpressing metastatic breast cancer that had progressed while receiving trastuzumab.
Experimental Design: Eligible patients had bi-dimensionally measurable or evaluable HER-2/neu-overexpressing metastatic breast cancer. HER-2/neu overexpression, defined as 2+ or 3+ by the HercepTest, was required. Patients had to have progressed despite prior trastuzumab-based therapy. Treatment consisted of celecoxib (400 mg twice daily) and trastuzumab.
Results: Twelve patients were enrolled (42% status post 1 regimen for metastatic disease 58% status post &gt; 2 prior regimens (range of 2–6). Eleven patients were evaluable. There were no responses. Median duration of treatment was 9 weeks. One patient had stable disease at 3 months but progressed at 6 months. A second patient stopped treatment at 3 months because of unresolved grade 2 rash, felt to be related to celecoxib. Toxicities were generally grade 1 or 2. One patient (8%) experienced grade 3 toxicity (abdominal pain).
Conclusions: Celecoxib combined with trastuzumab is well tolerated. However, this combination in patients with HER2/neu-overexpressing, trastuzumab-refractory disease, was not active.